Methods and devices for treating a disease with biotherapeutics

ABSTRACT

This disclosure features methods and devices for treating diseases with orally-delivered biotherapeutics.

RELATED APPLICATIONS

This application claims the benefit of the following patentapplications:

U.S. Ser. No. 62/769,496, filed Nov. 19, 2018, and entitled “IngestibleDevice With High Pressure Substance Delivery to the GastrointestinalTract”;

U.S. Ser. No. 62/818,731, filed Mar. 14, 2019, and entitled “IngestibleDevice With High Pressure Substance Delivery to the GastrointestinalTract”;

U.S. Ser. No. 62/819,513, filed Mar. 15, 2019, and entitled “IngestibleDevice With High Pressure Substance Delivery to the GastrointestinalTract”; and

U.S. Ser. No. 62/932,459, filed Nov. 7, 2019, and entitled “IngestibleDevice and Method of Use to Deliver Therapeutic Agent to theGastrointestinal Tract.”

The entire disclosure of each of these applications is incorporated byreference in its entirety.

FIELD

The disclosure generally relates to ingestible devices capable ofdelivering a dispensable substance, such as a therapeutic agent, as wellas related components, systems and methods.

BACKGROUND

The gastrointestinal (GI) tract generally provides a therapeutic mediumfor an individual's body. At times, it is desirable to dispensetherapeutic agents to the GI tract to treat a medical condition.

SUMMARY

The disclosure provides ingestible devices that can directly delivertherapeutic agents to desired tissue(s) of the GI tract of a subject,such as the submucosa, the mucosa, and/or the mucus layer of the GItract, and methods of using the same. The ingestible devices can delivertherapeutic agents in a safe, effective, and reliable manner. Thedisclosure also provides pharmaceutical compositions for use in methodsof treating a disease or condition in a subject in need thereof.

Ingestible devices of the present disclosure are configured to provideat least three different modes of direct delivery of therapeutic agentsto the GI tract of a subject, referred to herein as trans-epithelial,epithelial, and topical delivery. Direct delivery, as used herein,refers to a force-driven delivery mechanism.

Thus, in one aspect, this disclosure relates to trans-epithelialdelivery of a therapeutic agent to the GI tract of a subject.Accordingly, the disclosure provides an ingestible device that candirectly deliver a therapeutic agent past the epithelial cell layer ofthe mucosa of the GI tract of a subject to yield systemic exposure ofthe therapeutic agent to the subject. In such embodiments, theingestible device is configured to directly deliver the therapeuticagent past the epithelial cell layer of the mucosa and into thesubmucosa and/or into a region of the mucosa beneath the epitheliallayer (e.g., into the lamina propria) of the GI tract, where it isavailable for systemic uptake. This can be particularly relevant whenthe oral bioavailability of the therapeutic agent is otherwise low. Insome embodiments, systemic exposure of the therapeutic agent is achievedby trans-epithelial delivery of the therapeutic agent into the submucosaand/or into a region of the mucosa beneath the epithelial layer (e.g.,into the lamina propria) of the small intestine, for example, in theduodenum, the jejunum, and/or the ileum. In further embodiments, thetrans-epithelial delivery directly delivers the therapeutic agent intothe submucosa submucosa and/or into a region of the mucosa beneath theepithelial layer (e.g., into the lamina propria) of the GI tract suchthat the percent systemic uptake of the trans-epithelial deliveryrelative to intravenous or subcutaneous administration is at least about10% (e.g., at least about 15%, at least about 20%, at least about 25% ormore).

Without wishing to be bound by theory, it is believed thattrans-epithelial delivery to the submucosa and/or into a region of themucosa beneath the epithelial layer (e.g., into the lamina propria) ofthe GI tract is achieved by using an appropriate value for one or moreperformance parameters associated with the ingestible device configuredfor such use. Such performance parameters include, for example, internalpressure of the ingestible device, peak fluid pressure of the ingestibledevice, nozzle pressure of the ingestible device, peak jet power of thedispensable substance (e.g., a pharmaceutical formulation containing thetherapeutic agent) delivered from the ingestible device, peak jetvelocity of the dispensable substance (e.g., a pharmaceuticalformulation containing the therapeutic agent) delivered from theingestible device, peak jet pressure of the dispensable substance (e.g.,a pharmaceutical formulation containing the therapeutic agent) deliveredfrom the ingestible device, peak jet force of the dispensable substance(e.g., a pharmaceutical formulation containing the therapeutic agent)delivered from the ingestible device, peak jet stable length of thedispensable substance (e.g., a pharmaceutical formulation containing thetherapeutic agent) delivered from the ingestible device, nozzle shape,nozzle length and nozzle diameter.

As an example, in some embodiments, the ingestible device is configuredfor trans-epithelial delivery and may provide/exhibit one or more of thefollowing properties. The ingestible device is configured to deliver thedispensable substance to tissue of the GI tract of a subject at a peakjet power of from about one Watt to about three Watts. The ingestibledevice has a drive force generator that provides an internal pressure offrom about 225 psig to about 400 psig. The ingestible device containsthe dispensable substance at a peak fluid pressure of from about 200psig to about 375 psig. The ingestible device is configured to deliverthe dispensable substance at a peak jet velocity of from about 25 metersper second to about 45 meters per second. The ingestible device isconfigured to deliver the dispensable substance as a jet having jetstable length of at least about one millimeter. The ingestible device isconfigured to deliver the dispensable substance to tissue of the GItract of a subject at a peak jet pressure of from about 100 psig toabout 250 psig. The ingestible device is configured to deliver thedispensable substance to tissue of the GI tract of a subject at a peakjet force of from about 0.09 N to about 0.15 N. The ingestible devicehas one or more nozzles, each having a diameter of from about 0.1millimeter to about two millimeters and/or a length of from about onemillimeter to about five millimeters.

In another aspect, this disclosure relates to epithelial delivery of atherapeutic agent to the GI tract of a subject. Accordingly, thedisclosure provides an ingestible device configured to directly deliverthe therapeutic agent into the mucus and/or onto the epithelial layer,but not past the epithelial layer of the mucosa, of the small or largeintestine, from which it can act locally, and in some cases away fromthe site of direct delivery. In some embodiments, the device isconfigured so that the therapeutic agent is delivered from the devicewith sufficient force to provide the epithelial delivery, the forcebeing lower than that required for trans-epithelial delivery.

In yet another aspect, this disclosure relates to topical delivery of atherapeutic agent to the GI tract of a subject. Accordingly, thedisclosure provides an ingestible device configured to deliver thetherapeutic agent into the lumen and/or onto the mucus or other surfaceof the GI tract facing the lumen of the small or large intestine, fromwhich it can act locally, and in some cases away from the site ofdelivery. In some embodiments, the device is configured so that thetherapeutic agent is delivered from the device with sufficient force sothat the therapeutic agent is delivered topically, the force being lowerthan that required for the epithelial or the trans-epithelial delivery.

The ingestible device, whether configured for trans-epithelial,epithelial or topical delivery, can have a streamlined and/or relativelysimple mechanical design, be relatively small, and/or be inexpensive tomanufacture. In general, the device protects a dispensable substance(e.g., a therapeutic agent, or a pharmaceutical formulation comprisingthe therapeutic agent) until the device reaches a desired location ofthe subject. As an example, the device can be designed to deliverdispensable substance to a desired location in the GI tract of asubject, and the device can be designed so that the dispensablesubstance is not subject to constituents of the GI tract (e.g., acids,enzymes) prior to reaching the desired location in the GI tract. Asanother example, the device can be designed to deliver dispensablesubstance such that the therapeutic properties of the dispensablesubstance are not altered during delivery (e.g., the dispensablesubstance is a therapeutic agent that binds its therapeutic target afterdelivery).

The present disclosure provides ingestible devices that can directlydeliver therapeutic agents to desired tissue(s) of the GI tract of asubject (such as the submucosa, the mucosa, and/or the mucus layer ofthe GI tract), e.g., to treat a particular class of disease, or aspecific disease. Relatedly, methods of using the device to deliver thetherapeutic agents to desired tissue(s) of the GI tract, e.g., to treata particular class of disease, or a specific disease, are disclosed.These disclosures also inherently provide disclosures of correspondingmedical uses—that is, disclosures of the recited therapeutic agents foruse in a method of treating the recited class of disease, or specificdisease, by using the device to deliver the recited agents to desiredtissue(s) of the GI tract of a subject.

First Group of Aspects of the Disclosure

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent; and an opening in the housing configuredto fluidly connect the dispensable substance to an environment outsidethe housing via the opening, wherein the ingestible device is configuredto directly deliver the dispensable substance to the GI tract of asubject via trans-epithelial delivery. The ingestible device may beconfigured to directly deliver the dispensable substance into the laminapropria of the GI tract of the subject, and/or the ingestible device maybe to directly deliver the dispensable substance into the submucosa ofthe GI tract of the subject.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent; and an opening in the housing configuredto fluidly connect the dispensable substance to an environment outsidethe housing via the opening, wherein the ingestible device is configuredto deliver the dispensable substance to tissue of the GI tract of asubject as a jet with a peak jet power of from about one Watt to aboutthree Watts. The peak jet power may be from about 1.3 Watts to about 2.8Watts, from about 1.5 Watts to about 2.5 Watts, or about 2.3 Watts.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent; and an opening in the housing configuredto fluidly connect the dispensable substance to an environment outsidethe housing via the opening, wherein the ingestible device is configuredto provide an internal pressure of from about 225 psig to about 425psig. The internal pressure may be from about 250 psig to about 400psig, or from about 300 psig to about 375 psig.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent; and an opening in the housing configuredto fluidly connect the dispensable substance to an environment outsidethe housing via the opening, wherein the ingestible device is configuredto contain the dispensable substance at a peak fluid pressure of fromabout 200 psig to about 400 psig.

The ingestible device may be configured to deliver the dispensablesubstance at a mean jet velocity of from about 25 m/s to about 35 m/s.

The ingestible device may be configured to contain the dispensablesubstance at a peak fluid pressure of: from about 200 psig to about 375psig; at least about 220 psig; from about 220 psig to about 375 psig;from about 220 psig to about 350 psig; at least about 225 psig; fromabout 225 psig to about 375 psig; from about 225 psig to about 350 psig;from about 225 psig to about 325 psig; at least about 250 psig; fromabout 250 psig to about 375 psig; from about 250 psig to about 350 psig;from about 250 psig to about 325 psig; at least about 275 psig; fromabout 275 psig to about 375 psig; from about 275 psig to about 350 psig;from about 275 psig to about 325 psig; from about 280 psig to about 320psig; at least about 300 psig; from about 300 psig to about 375 psig;from about 300 psig to about 350 psig; from about 300 psig to about 325psig; about 200 psig; about 210 psig; about 220 psig; about 230 psig;about 240 psig; about 250 psig; about 260 psig; about 270 psig; about280 psig; about 290 psig; about 300 psig; about 310 psig; or about 320psig.

The ingestible device may be configured to deliver the dispensablesubstance at a mean jet velocity of from about 20 m/s to about 30 m/s,from about 25 m/s to about 30 m/s, or from about 27 m/s to about 30 m/sor from about 28 m/s to about 30 m/s.

The opening in the ingestible device may comprise a nozzle openinghaving a diameter of from about 0.1 mm to about 2 mm, from about 0.1 mmto about 1 mm, from about 0.2 mm to about 0.8 mm, from about 0.3 mm toabout 0.5 mm, from about 0.3 mm to about 0.4 mm, or about 0.35 mm.

The ingestible device may be 1 to 5 nozzles, 2 to 4 nozzles or 2nozzles.

The ingestible device may be configured to release a dispensablesubstance volume ranging from about 50 microliters to about 500microliters, from about 100 microliters to about 450 microliters, fromabout 200 microliters to about 400 microliters, from 250 microliters toabout 400 microliters, or from about 300 microliters to about 400microliters.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent; and an opening in the housing configuredto fluidly connect the dispensable substance to an environment outsidethe housing via the opening, wherein the ingestible device is configuredto contain the dispensable substance at a peak fluid pressure of fromabout 150 psig to about 350 psig. The ingestible device may beconfigured to deliver the dispensable substance at a mean jet velocityof from about 20 m/s to about 30 m/s, about 20 m/s, 21 m/s, 22 m/s 23m/s, 24 m/s, 25 m/s, 26 m/s, 27 m/s, 28 m/s, 29 m/s or 30 m/s.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent; and an opening in the housing configuredto fluidly connect the dispensable substance to an environment outsidethe housing via the opening, wherein the ingestible device is configuredto deliver the dispensable substance at a peak jet velocity of fromabout 25 meters per second to about 45 meters per second. The peak jetvelocity may be from about 30 meters per second to about 42 meters persecond, or from about 34 meters per second to about 39 meters persecond.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent; and an opening in the housing configuredto fluidly connect the dispensable substance to an environment outsidethe housing via the opening, wherein the ingestible device is configuredto deliver the dispensable substance as a jet having jet stable lengthof at least about 0.5 millimeter. The jet stable length may be from 0.5millimeter to 20 millimeters, from about 2 millimeters to 20millimeters, or from about 5 millimeters to 20 millimeters.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent; and an opening in the housing configuredto fluidly connect the dispensable substance to an environment outsidethe housing via the opening, wherein the ingestible device is configuredto deliver the dispensable substance to tissue of the GI tract of asubject at a peak jet pressure of from about 100 psig to about 250 psig.The peak jet pressure may be from about 140 psig to about 225 psig, orfrom about 180 psig to about 205 psig.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent; and an opening in the housing configuredto fluidly connect the dispensable substance to an environment outsidethe housing via the opening, wherein the ingestible device is configuredto deliver the dispensable substance to tissue of the GI tract of asubject at a peak jet force of from about 0.09 N to about 0.15 N. Theingestible device may be configured to deliver the dispensable substanceto tissue of the GI tract of a subject at a peak jet force of from about0.1 N to about 0.14 N, or from about 0.11 N to about 0.14 N.

The ingestible device may comprises a nozzle, and the opening maycomprise a nozzle opening. The nozzle may have a nozzle diameter of fromabout 0.1 millimeter to about two millimeters, and/or a nozzle length offrom about one millimeter to about five millimeters.

The ingestible device may comprise a plurality of nozzles. The nozzlesmay be directed perpendicular to a longitudinal axis of the ingestibledevice. The nozzles may be uniformly distributed relative to acircumference of the ingestible device. The plurality of nozzles maycomprise an even number of nozzles or an odd number of nozzles. Theplurality of nozzles comprises two nozzles.

The ingestible device may be configured to deliver from about 20microliters to about 800 microliters of the dispensable substancethrough each nozzle.

The ingestible device may further include the dispensable substance,wherein the dispensable substance comprises a fluid. The ingestibledevice may further include the dispensable substance, wherein thedispensable substance comprises a fluid. The dispensable substance maycomprise a therapeutic agent. The dispensable substance may comprise asolution. The dispensable substance may comprise a suspension. Thedispensable substance may have a viscosity of less than or equal to 10cP. The dispensable substance may have a viscosity of at least about 0.8cP. The dispensable substance may a viscosity of at most about 8 cP orat most about 9 cP.

The jet may have an average jet diameter of from about 0.1 millimeter toabout two millimeters.

The jet may have a jet stable length of at least about 0.5 millimeter.

The ingestible device may contain from about 50 microliters to about 800microliters of the dispensable substance.

The ingestible device may be configured to deliver from about 50microliters to about 800 microliters of the dispensable substance.

The ingestible device may further comprise a drive force generatorconfigured to apply a force to the dispensable substance to force thedispensable substance out of the ingestible device via the opening. Thedrive force generator may comprise a member selected from the groupconsisting of a spring, a gas cell, a compressed gas, and a liquid-gasmixture. The ingestible device may comprise chemicals configured toreact to provide a gas as the drive force generator. The drive forcegenerator may be configured to provide an internal pressure of fromabout 225 psig to about 400 psig.

The ingestible device may further comprise a drive coupling configuredto transfer force from the drive force generator to the dispensablesubstance. The drive coupling may comprise a member selected from thegroup consisting of a piston and a membrane.

The ingestible device may further comprise a restraining mechanismhaving a first state and a second state, wherein, when the restrainingmechanism is in its first state, the restraining mechanism prevents thedispensable substance from being delivered out of the ingestible device.In some embodiments, when the restraining mechanism is in its secondstate, the restraining mechanism does not prevent the dispensablesubstance from being delivered out of the ingestible device. Theingestible device may be configured so that, when the restrainingmechanism is in its first state, the drive force generator does notapply an internal pressure to the dispensable substance. The ingestibledevice may be configured so that, when the restraining mechanism is inits first state, the drive force generator applies an internal pressureto the dispensable substance. The restraining mechanism may comprise amaterial selected from the group consisting of a degradable material, anerodible material and a dissolvable material. The restraining mechanismmay comprise an enteric material. The restraining mechanism may compriseat least one member selected from the group consisting of a seal, a pin,a dowel, a clasp, a clamp, a flange, and a rivet. The restrainingmechanism may comprise a cap. The cap may be located at a distal end ofthe ingestible device.

The ingestible device may be configured to directly deliver thedispensable substance to the GI tract of a subject via trans-epithelialdelivery.

The ingestible device may be configured to deliver the dispensablesubstance to tissue of the GI tract of a subject as a jet with a peakjet power of from about one Watt to about three Watts.

The ingestible device may be configured to provide an internal pressureof from about 225 psig to about 425 psig.

The ingestible device may be configured to contain the dispensablesubstance at a peak fluid pressure of from about 200 psig to about 375psig.

The ingestible device may be configured to contain the dispensablesubstance at a peak fluid pressure of from about 150 psig to about 350psig.

The ingestible device may be configured to deliver the dispensablesubstance at a peak jet velocity of from about 25 meters per second toabout 45 meters per second.

The ingestible device may be configured to deliver the dispensablesubstance as a jet having jet stable length of at least about 0.5millimeter.

The ingestible device may be configured to deliver the dispensablesubstance at a peak jet pressure of from about 100 psig to about 250psig.

The ingestible device may be configured to deliver the dispensablesubstance to tissue of the GI tract of a subject at a peak jet force offrom about 0.09 N to about 0.15.

The housing has a length of from about 20 mm to about 28 mm.

The housing may have a diameter of from about 7 mm to about 12 mm.

The housing may comprise a wall having a wall thickness of from about0.5 mm to about 1 mm.

A ratio of the length of the housing to the width of the housing may beselected from the group consisting of: from about 0.75 to about 4; fromabout 1 to about 3; and from about 1 to about 2.

In some embodiments, at least one of the following holds: the housingcomprises end regions that are spline-shaped; the housing comprises endregions that are spherical; the housing comprises an end round of fromabout 1 mm to about 2 mm; the housing comprises an end round of fromabout 4 mm to about 4.5 mm; the housing comprises an end round that isfrom about 4.9 to about 5 mm; and the housing comprises an end round offrom about 5.4 mm to about 5.6 mm.

The housing may have an internal volume of from about 700 μL to about1700 μL.

The housing may have a fluid volume from about 50 μL to about 800 μL.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing;

an opening in the housing configured to fluidly connect the dispensablesubstance to an environment outside the housing via the opening; a driveforce generator configured to provide a force to the dispensablesubstance to deliver the dispensable substance through the opening; adrive force coupling configured to transfer the force from the driveforce generator to the dispensable substance; and a restrainingmechanism having a first state in which the restraining mechanismprevents the dispensable substance from being delivered out of theingestible device.

The drive force generator may comprise a member selected from the groupconsisting of a spring, a gas cell, a compressed gas, and a liquid-gasmixture. The ingestible device may comprise chemicals configured toreact to provide a gas as the drive force generator. The drive forcegenerator may be configured to provide an internal pressure of fromabout 225 psig to about 400 psig.

The drive coupling may comprise a member selected from the groupconsisting of a piston and a membrane.

In some embodiments, when the restraining mechanism is in its firststate, the drive force generator does not apply an internal pressure tothe dispensable substance. In certain embodiments, when the restrainingmechanism is in its first state, the drive force generator applies aninternal pressure to the dispensable substance. The restrainingmechanism may have second state different from its first state, and,when the restraining mechanism is in its second state, the restrainingmechanism does not prevent the dispensable substance from beingdelivered out of the ingestible device. The restraining mechanism maycomprise a material selected from the group consisting of a degradablematerial, an erodible material and a dissolvable material. Therestraining mechanism may comprise an enteric material. The restrainingmechanism may comprise at least one member selected from the groupconsisting of a seal, a pin, a band, a dowel, a clasp, a clamp, aflange, and a rivet. The restraining mechanism may comprise a cap. Thecap may be located at a distal end of the ingestible device.

The housing may have a length of from about 20 mm to about 28 mm, fromabout 21 mm to about 27 mm, about 26 mm, or about 23.3 mm.

The housing may have a diameter of from about 7 mm to about 12 mm, fromabout 8 mm to about 11 mm, about 11 mm, about 9.9 mm, or about 8.5 mm.

A ratio of the length of the housing to the width of the housing may befrom about 0.75 to about 4, from about 1 to about 3, or from about 1 toabout 2.

The housing may comprise a wall having a wall thickness of from about0.5 mm to about 1 mm, from about 0.6 mm to about 0.9 mm, about 0.8 mm,or about 0.7 m.

The housing may have end regions that are spline-shaped or that arespherical.

The housing may comprise an end round of from about 1 mm to about 2 mm,about 1.5 mm, from about 4 mm to about 4.5 mm, about 4.25 mm, from about4.9 to about 5 mm, about 4.95 mm, from about 5.4 mm to about 5.6 mm, orabout 5.5 mm.

The housing may comprise an internal volume of from about 700 μL toabout 1700 μL, from about 750 μL to about 1650 μL, from about 800 μL toabout 1600 μL, or from about 850 μL to about 1550 μL.

The housing may comprise a fluid volume of from about 50 μL to about 800μL, from about 100 μL to about 600 μL, or from about 200 μL to about 400μL.

The ingestible device may comprise a plurality of openings in thehousing configured to fluidly connect the dispensable substance to anenvironment outside the housing via the opening. The plurality ofopenings may comprise an even number of openings or an odd number ofopenings. The plurality of openings may comprise a member selected fromgroup consisting of 2 openings, 3 openings, 4 openings, 5 openings, 6openings, 7 openings and 8 openings. Each opening may comprise a nozzleopening.

The opening may comprise a nozzle opening having a diameter from about0.1 mm to about 2 mm, from about 0.1 mm to about 1 mm, from about 0.2 mmto about 0.8 mm, or from about 0.3 mm to about 0.4 mm.

The ingestible device may comprise a nozzle having a length of fromabout 1 mm to about 5 mm, from about 2 mm to about 5 mm, or from about 3mm to about 5 mm.

The ingestible device may comprise a plurality of openings in thehousing configured to fluidly connect the dispensable substance to anenvironment outside the housing via the opening, and the ingestibledevice is configured to provide a delivered fluid volume per opening fordelivery of dispensable substance of from about 25 μL to about 400 μL.

The ingestible device may comprise a plurality of openings in thehousing configured to fluidly connect the dispensable substance to anenvironment outside the housing via the opening, and the ingestibledevice is configured to provide a delivered fluid volume per opening fordelivery of dispensable substance of from about 25 μL to about 300 μL.

The ingestible device may comprise a plurality of openings in thehousing configured to fluidly connect the dispensable substance to anenvironment outside the housing via the opening, and the ingestibledevice may be configured to provide a delivered fluid volume per openingfor delivery of dispensable substance of from about 100 μL to about 300μL.

The ingestible device may further comprise the dispensable substance.The dispensable substance may comprise a fluid. The dispensablesubstance may comprise a liquid. The dispensable substance may comprisea therapeutic agent. The dispensable substance may comprise a solution.The dispensable substance may comprise a suspension.

The ingestible device may be configured to directly deliver thedispensable substance to the GI tract of a subject via trans-epithelialdelivery.

The ingestible device may be configured to deliver the dispensablesubstance to tissue of the GI tract of a subject as a jet with a peakjet power of from about one Watt to about three Watts.

The ingestible device may be configured to ingestible device isconfigured to provide an internal pressure of from about 225 psig toabout 425 psig.

The ingestible device may be configured to contain the dispensablesubstance at a peak fluid pressure of from about 200 psig to about 375psig.

The ingestible device may be configured to deliver the dispensablesubstance at a peak jet velocity of from about 25 meters per second toabout 45 meters per second.

The ingestible device may be configured to deliver the dispensablesubstance as a jet having jet stable length of at least about 0.5millimeter.

The ingestible device may be configured to deliver the dispensablesubstance at a peak jet pressure of from about 100 psig to about 250psig.

The ingestible device may be configured to deliver the dispensablesubstance to tissue of the GI tract of a subject at a peak jet force offrom about 0.09 N to about 0.15.

In a general aspect, the disclosure provides an ingestible device,comprising: a housing configured to contain a dispensable substancecomprising a therapeutic agent, wherein the dispensable substance is afluid; and an opening in the housing configured to fluidly connect thedispensable substance to an environment outside the housing via theopening, wherein the ingestible device is configured fortrans-epithelial delivery of the dispensable subject to the GI tract ofa subject as a jet.

The ingestible device may be configured to provide an internal pressureof from about 220 psig to about 420 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 200 psig to about 400 psig.

The ingestible device may be configured to provide an internal pressureof from about 220 psig to about 395 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 200 psig to about 375 psig.

The ingestible device may be configured to provide an internal pressureof from about 220 psig to about 350 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 200 psig to about 330 psig.

The ingestible device may be configured to provide an internal pressureof from about 225 psig to about 400 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 205 psig to about 380 psig.

The ingestible device may be configured to provide an internal pressureof from about 230 psig to about 370 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 210 psig to about 350 psig.

The ingestible device may be configured to provide an internal pressureof from about 240 psig to about 370 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 220 psig to about 350 psig.

The ingestible device may be configured to provide an internal pressureof from about 250 psig to about 375 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 230 psig to about 355 psig.

The ingestible device may be configured to provide an internal pressureof from about 250 psig to about 350 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 230 psig to about 330 psig.

The ingestible device may be configured to provide an internal pressureof from about 270 psig to about 370 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 250 psig to about 350 psig.

The ingestible device may be configured to provide an internal pressureof from about 270 psig to about 350 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 250 psig to about 330 psig.

The ingestible device may be configured to provide an internal pressureof from about 300 psig to about 340 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 280 psig to about 320 psig.

The ingestible device may be configured to provide an internal pressureof from about 310 psig to about 340 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 290 psig to about 320 psig.

The ingestible device may be configured to provide an internal pressureof from about 320 psig to about 340 psig. The ingestible device may beconfigured to contain the dispensable substance at a peak fluid pressureof from about 300 psig to about 320 psig.

The ingestible device may be configured to provide an internal pressureof about 220 psig, about 230 psig, about 240 psig, about 250 psig, about260 psig, about 270 psig, about 280 psig, about 290 psig, about 300psig, about 310 psig, about 320 psig, about 330 psig, about 340 psig orabout 350 psig. The ingestible device may be configured to contain thedispensable substance at a peak fluid pressure of about 200 psig, about210 psig, about 220 psig, about 230 psig, about 240 psig, about 250psig, about 260 psig, about 270 psig, about 280 psig, about 290 psig,about 300 psig, about 310 psig, about 320 psig or about 330 psig.

The ingestible device may be configured to deliver the dispensablesubstance as the jet with a peak jet velocity of from about 25 m/s toabout 45 m/s, from about 25 m/s to about 40 m/s, from about 30 m/s toabout 40 m/s, from about 32 m/s to about 40 m/s, or from about 35 m/s toabout 40 m/s.

The ingestible device may be configured to deliver the dispensablesubstance to the GI tract of the subject as the jet with a peak jetpower of from about 1 Watt to about 3 Watts. The ingestible device maybe configured to contain the dispensable substance as the jet with apeak fluid pressure of from about 200 psig to about 375 psig. Theingestible device may be configured to deliver the dispensable substanceto the GI tract of the subject as the jet with a peak jet pressure offrom about 100 psig to about 250 psig, or with a peak jet force of fromabout 0.09 N to about 0.15 N.

The ingestible device of claim 191 or claim 194, wherein the ingestibledevice is configured may be configured to deliver the dispensablesubstance to the GI tract of the subject as the jet with a peak jetpower of from about 1.3 Watts to about 2.8 Watts. The ingestible devicemay be configured to contain the dispensable substance as the jet with apeak fluid pressure of from about 220 psig to about 350 psig. Theingestible device may be configured to deliver the dispensable substanceto the GI tract of the subject as the jet with a peak jet pressure offrom about 140 psig to about 225 psig, or with a peak jet force of fromabout 0.1 N to about 0.14 N.

The ingestible device o may be configured to deliver the dispensablesubstance to the GI tract of the subject as the jet with a peak jetpower of from about 1.5 Watts to about 2.5 Watts. The ingestible devicemay be configured to contain the dispensable substance as the jet with apeak fluid pressure of from about 280 psig to about 320 psig. Theingestible device may be configured to deliver the dispensable substanceto the GI tract of the subject as the jet with a peak jet pressure offrom about 180 psig to about 205 psig, or with a peak jet force of fromabout 0.11 N to about 0.14 N.

In some embodiments, the ingestible device may be configured to deliverthe dispensable substance as the jet with a mean jet velocity of fromabout 18 m/s to about 30 m/s, from about 19 m/s to about 30 m/s, fromabout 20 m/s to about 30 m/s, from about 21 m/s to about 30 m/s, fromabout 22 m/s to about 30 m/s, from about 23 m/s to about 30 m/s, fromabout 24 m/s to about 30 m/s, from about 25 m/s to about 30 m/s, fromabout 25 m/s to about 28 m/s, about 20 m/s, 21 m/s, 22 m/s 23 m/s, 24m/s, 25 m/s, 26 m/s, 27 m/s, 28 m/s, 29 m/s or 30 m/s.

In certain embodiments, the ingestible device may be configured todeliver the dispensable substance as the jet with a mean jet velocity offrom about 25 m/s to about 35 m/s.

In some embodiments: the opening in the housing is a plurality ofopenings, each opening comprising a nozzle, or the opening in thehousing comprises a plurality of nozzles; and each nozzle has an orificeto fluidly connect the dispensable substance to the environment outsidethe housing and to release the dispensable substance from the ingestibledevice as a jet. Each nozzle orifice may be directed perpendicular to alongitudinal axis of the ingestible device. Each nozzle orifice may havea diameter of from about 0.1 mm to about 2 mm, each jet when dispensedfrom each nozzle orifice has a diameter of from about 0.1 mm to about 2mm, or both. Each nozzle orifice may have a diameter of from about 0.1mm to about 1 mm, each jet when dispensed from each nozzle orifice has adiameter of from about 0.1 mm to about 1 mm, or both. Each nozzleorifice may have a diameter of from about 0.2 mm to about 0.8 mm, eachjet when dispensed from each nozzle has a diameter of from about 0.2 mmto about 0.8 mm, or both. Each nozzle orifice may have a diameter offrom about 0.3 mm to about 0.5 mm, each jet when dispensed from eachnozzle may have a diameter of from about 0.3 mm to about 0.5 mm, orboth. Each nozzle orifice may have a diameter of from about 0.3 mm toabout 0.4 mm, each jet when dispensed from each nozzle may have adiameter of from about 0.3 mm to about 0.4 mm, or both. Each nozzleorifice may have a diameter of about 0.35 mm, each jet when dispensedfrom each nozzle may have a diameter of about 0.35 mm, or both.

The ingestible device may be configured to deliver the dispensablesubstance as the jet with a jet stable length of at least about 0.5 mm.

The ingestible device may be configured to deliver the dispensablesubstance as the jet with a jet stable length of from about 0.5 mm toabout 20 mm.

The ingestible device may be configured to deliver the dispensablesubstance as the jet with a jet stable length of from about 2 mm toabout 20 mm.

The ingestible device may be configured to deliver the dispensablesubstance as the jet with a jet stable length of from about 5 mm toabout 20 mm.

The ingestible device may comprise at least two nozzles, and the atleast two nozzles may be uniformly distributed relative to acircumference of the ingestible device.

The ingestible device may comprise an even number of nozzles or an oddnumber of nozzles.

The ingestible device may comprise 2 nozzles, 3 nozzles, 4 nozzles, 5nozzles, 6 nozzles, 7 nozzles or 8 nozzles.

Each nozzle may have a length of from about 0.5 mm to about 5 mm, about1 mm to about 5 mm, about 2 mm to about 5 mm, or about 3 mm to about 5mm.

Each nozzle may have a length of from about 1 mm to about 4 mm.

Each nozzle may have a length of from about 1 mm to about 3 mm.

The ingestible device may be configured to release a dispensablesubstance volume ranging from about 50 microliters to about 800microliters, about 50 microliters to about 500 microliters, from about100 microliters to about 450 microliters, from about 200 microliters toabout 400 microliters, from 250 microliters to about 400 microliters, orfrom about 300 microliters to about 400 microliters.

The ingestible device may be configured to release a dispensablesubstance volume ranging from about 200 microliters to about 400microliters.

The ingestible device may comprise: a drive force generator configuredto provide a force to the dispensable substance to deliver thedispensable substance through the opening or nozzle orifice; a driveforce coupling configured to transfer the force from the drive forcegenerator to the dispensable substance; and a restraining mechanismhaving a first state in which the restraining mechanism prevents thedispensable substance from being delivered out of the ingestible device;and a second state in which the restraining mechanism does not preventthe dispensable substance from being delivered out of the ingestibledevice.

In some embodiments, when the restraining mechanism is in its firststate, the drive force generator does not apply an internal pressure tothe dispensable substance.

In certain embodiments, when the restraining mechanism is in its firststate, the drive force generator applies an internal pressure to thedispensable substance.

The drive force generator may comprise a member selected from the groupconsisting of a spring, a gas cell, a compressed gas, and a liquid-gasmixture.

The ingestible device may comprise chemicals configured to react toprovide a gas as the drive force generator.

The drive force generator may be configured to provide the internalpressure.

The drive coupling may comprise a member selected from the groupconsisting of a piston and a membrane.

The restraining mechanism may have second state different from its firststate, and, when the restraining mechanism is in its second state, therestraining mechanism does not prevent the dispensable substance frombeing delivered out of the ingestible device. The restraining mechanismmay comprise a material selected from the group consisting of adegradable material, an erodible material and a dissolvable material.The restraining mechanism may comprise an enteric material. Therestraining mechanism may comprise at least one member selected from thegroup consisting of a seal, a pin, a band, a dowel, a clasp, a clamp, aflange, and a rivet. The restraining mechanism may comprise a cap. Thecap may be located at a distal end of the ingestible device.

The housing may have a length of from about 20 mm to about 28 mm, fromabout 21 mm to about 27 mm, about 26 mm, or about 23.3 mm.

The housing may have a diameter of from about 7 mm to about 12 mm, fromabout 8 mm to about 11 mm, about 11 mm, about 9.9 mm, or about 8.5 mm.

The housing may comprise a wall having a wall thickness of from about0.5 mm to about 1 mm, from about 0.6 mm to about 0.9 mm, about 0.8 mm,or about 0.7 mm.

The housing may have end regions that are spline-shaped or that arespherical.

The housing may have an end round of from about 1 mm to about 2 mm,about 1.5 mm, from about 4 mm to about 4.5 mm, about 4.25 mm, from about4.9 to about 5 mm, about 4.95 mm, from about 5.4 mm to about 5.6 mm, orabout 5.5 mm.

In some embodiments, at least one of the following holds: the housinghas end regions that are spline-shaped; the housing has end regions thatare spherical; the housing has an end round of from about 1 mm to about2 mm; the housing has an end round of from about 4 mm to about 4.5 mm;the housing has an end round that is from about 4.9 to about 5 mm; andthe housing has an end round of from about 5.4 mm to about 5.6 mm.

The housing may have an internal volume of from about 700 microliters toabout 1700 microliters, from about 750 microliters to about 1650microliters, from about 800 microliters to about 1600 microliters, orfrom about 850 microliters to about 1550 microliters.

The ingestible device may have a fluid volume from about 50 microlitersto about 800 microliters, from about 100 microliters to about 600microliters, or from about 200 microliters to about 400 microliters.

The ingestible device may be configured to deliver from about 20microliters to about 800 microliters of the dispensable substancethrough each opening or nozzle orifice, from about 25 microliters toabout 400 microliters of the dispensable substance through each openingor nozzle orifice, from about 25 microliters to about 300 microliters ofthe dispensable substance through each opening or nozzle orifice, orfrom about 100 microliters to about 300 microliters of the dispensablesubstance through each nozzle.

A ratio of the length of the housing to the width of the housing may befrom about 0.75 to about 4, from about 1 to about 3, or from about 1 toabout 2.

The ingestible device may be configured as a 00 capsule.

The ingestible device may be configured as a 000 capsule.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to deliver a dispensable substance to the GI tractof the subject.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to directly deliver a dispensable substance to theGI tract of a subject via trans-epithelial delivery. The method maycomprise using the ingestible device to directly deliver the dispensablesubstance into the lamina propria of the GI tract of the subject, and/orusing the ingestible device to directly deliver the dispensablesubstance into the submucosa of the GI tract of the subject.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to directly deliver a dispensable substance totissue of the GI tract of a subject as a jet with a peak jet power offrom about one Watt to about three Watts. The peak jet power may be fromabout 1.3 Watts to about 2.8 Watts, from about 1.5 Watts to about 2.5Watts, or about 2.3 Watts.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to deliver a dispensable substance to the GI tractof a subject as a jet having a peak jet velocity of from about 25 metersper second to about 45 meters per second. The peak jet velocity may ofthe jet be from about 30 meters per second to about 42 meters persecond, or from about 34 meters per second to about 39 meters persecond.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to deliver a dispensable substance to the GI tractof a subject as a jet having a jet stable length of at least about 0.5millimeter. The jet may have jet stable length of from 0.5 millimeter to20 millimeters, from about 2 millimeters to 20 millimeters, or fromabout 5 millimeters to 20 millimeters.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to deliver a dispensable substance to the GI tractof a subject as a jet having a peak jet pressure of from about 100 psigto about 250 psig. The peak jet pressure may be from about 140 psig toabout 225 psig, or from about 180 psig to about 205 psig.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to deliver a dispensable substance to the GI tractof a subject as a jet having a peak jet force of from about 0.09 N toabout 0.15 N. The peak jet force may be from about 0.1 N to about 0.14N, or from about 0.11 N to about 0.14 N.

In such methods, the dispensable substance may have a viscosity of lessthan or equal to 10 cP, at least about 0.8 cP, at most about 8 cP,and/or or at most about 9 cP.

In such methods, the device may be configured as a 00 capsule, or thedevice may be configured as a 000 capsule.

Second Group of General Aspects of the Disclosure

In a general aspect, the disclosure provides an ingestible device,comprising: a housing; an opening in the housing configured to fluidlyconnect the dispensable substance to an environment outside the housingvia the opening; a drive force generator configured to provide a forceto the dispensable substance to deliver the dispensable substancethrough the opening; a drive force coupling configured to transfer theforce from the drive force generator to the dispensable substance; and arestraining mechanism having a first state in which the restrainingmechanism prevents the dispensable substance from being delivered out ofthe ingestible device, wherein at least one of the following holds: thedrive force generator is configured to provide an internal pressure offrom about 3.62 psig to about 21.76 psig; and the housing comprises atleast 25 openings configured to fluidly connect the dispensablesubstance to an environment outside the housing via the opening.

The drive force generator may comprise a member selected from the groupconsisting of a spring, a gas cell, a compressed gas, and a liquid-gasmixture. The ingestible device may comprise chemicals configured toreact to provide a gas as the drive force generator. The drive forcegenerator may be to provide an internal pressure of from about 3.62 psigto about 21.76 psig.

The drive coupling may comprise a member selected from the groupconsisting of a piston and a membrane.

In some embodiments, when the restraining mechanism is in its firststate, the drive force generator does not apply an internal pressure tothe dispensable substance. In certain embodiments, when the restrainingmechanism is in its first state, the drive force generator applies aninternal pressure to the dispensable substance. The restrainingmechanism may have a second state different from its first state, and,when the restraining mechanism is in its second state, the restrainingmechanism does not prevent the dispensable substance from beingdelivered out of the ingestible device. The restraining mechanism maycomprise a material selected from the group consisting of a degradablematerial, an erodible material and a dissolvable material. Therestraining mechanism may comprise an enteric material. The restrainingmechanism may comprise at least one member selected from the groupconsisting of a seal, a pin, a band, a dowel, a clasp, a clamp, aflange, and a rivet. The restraining mechanism may comprise a cap. Thecap may be located at a distal end of the ingestible device.

The housing may have a length of from about 20 mm to about 28 mm. fromabout 21 mm to about 27 mm, about 26 mm or about 23.3 mm.

The housing may have a diameter of from about 7 mm to about 12 mm, fromabout 8 mm to about 11 mm, about 11 mm, about 9.9 mm, or about 8.5 mm.

A ratio of the length of the housing to the width of the housing may befrom about 0.75 to about 4, from about 1 to about 3, or from about 1 toabout 2.

The housing may comprise a wall having a wall thickness of from about0.5 mm to about 1 mm, from about 0.6 mm to about 0.9 mm, about 0.8 mm,or about 0.7 mm.

The housing may comprise end regions that are spline-shaped or endregions that are spherical.

The housing may comprise an end round of from about 1 mm to about 2 mm,about 1.5 mm, from about 4 mm to about 4.5 mm, about 4.25 mm, from about4.9 to about 5 mm, about 4.95 mm, from about 5.4 mm to about 5.6 mm, orabout 5.5 mm.

The housing may comprise an internal volume of from about 700 μL toabout 1700 μL, from about 750 μL to about 1650 μL, from about 800 μL toabout 1600 μL, or from about 850 μL to about 1550 μL.

The housing may comprise a fluid volume from about 50 μL to about 800μL, from about 100 μL to about 600 μL, or from about 200 μL to about 400μL.

The ingestible may comprise a plurality of openings in the housingconfigured to fluidly connect the dispensable substance to anenvironment outside the housing via the opening. The plurality ofopenings may comprise an even number of openings or an odd number ofopenings. The plurality of openings may at least 25 openings, and/or theplurality of openings may comprise at most 50 openings. Each opening maycomprise a nozzle opening.

The opening may comprise a nozzle opening having a diameter from about 1mm to about 3 mm, at least about 1.5 mm, at least about 2 mm, and/or atmost about 2.5 mm.

The ingestible device may comprise a nozzle having a length of fromabout 1 mm to about 5 mm, from about 2 mm to about 5 mm, or from about 3mm to about 5 mm.

The ingestible may comprise a plurality of openings in the housingconfigured to fluidly connect the dispensable substance to anenvironment outside the housing via the opening, and the ingestibledevice is configured to provide a delivered fluid volume per opening fordelivery of dispensable substance of from about 25 μL to about 400 μL.

The ingestible device may comprise a plurality of openings in thehousing configured to fluidly connect the dispensable substance to anenvironment outside the housing via the opening, and the ingestibledevice is configured to provide a delivered fluid volume per opening fordelivery of dispensable substance of from about 25 μL to about 300 μL.

The may comprise a plurality of openings in the housing configured tofluidly connect the dispensable substance to an environment outside thehousing via the opening, and the ingestible device is configured toprovide a delivered fluid volume per opening for delivery of dispensablesubstance of from about 100 μL to about 300 μL.

The ingestible may further comprise the dispensable substance. Thedispensable substance may comprise a fluid. The dispensable substancemay comprise a liquid. The dispensable substance may comprise atherapeutic agent. The dispensable substance may comprise a solution.The dispensable substance may comprise a suspension. The dispensablesubstance may have a viscosity of less than or equal to 10 cP, of atleast about 0.8 cP, of at most about 8 cP, and/or at most about 9 cP.

The ingestible may be configured to directly deliver the dispensablesubstance to the GI tract of a subject via epithelial delivery.

The ingestible device may be configured to deliver the dispensablesubstance to tissue of the GI tract of a subject as a jet with a peakjet power of from about 1 mW to about 4 mW.

The ingestible d may be configured to contain the dispensable substanceat a peak fluid pressure of from about 3.62 psig to about 21.76 psig.

The ingestible device may be configured to deliver the dispensablesubstance as a jet having a peak jet velocity of from about 2 meters persecond to about 20 meters per second.

The ingestible device may be configured to deliver the dispensablesubstance as a jet having a peak jet pressure of from about 2 psig toabout 10 psig.

The ingestible device o may be configured to deliver the dispensablesubstance to tissue of the GI tract of a subject as a jet having a peakjet force of from about 0.05 mN to about 2 mN.

The ingestible device configured as a 00 capsule.

The ingestible device may be configured as a 000 capsule.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to directly deliver a dispensable substance to theGI tract of a subject via epithelial delivery.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to directly deliver a dispensable substance totissue of the GI tract of a subject as a jet with a peak jet power offrom about 1 mW to about 4 mW.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to deliver a dispensable substance to the GI tractof a subject as a jet having a peak jet velocity of from about 2 metersper second to about 20 meters per second.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to deliver a dispensable substance to the GI tractof a subject as a jet having a peak jet force of from about 0.05 mN toabout 2 mN.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to directly deliver a dispensable substance to theGI tract of a subject via epithelial delivery, wherein the ingestibledevice comprises: a housing; an opening in the housing configured tofluidly connect the dispensable substance to an environment outside thehousing via the opening; a drive force generator configured to provide aforce to the dispensable substance to deliver the dispensable substancethrough the opening; a drive force coupling configured to transfer theforce from the drive force generator to the dispensable substance; and arestraining mechanism having a first state in which the restrainingmechanism prevents the dispensable substance from being delivered out ofthe ingestible device.

The drive force generator may comprise a member selected from the groupconsisting of a spring, a gas cell, a compressed gas, and a liquid-gasmixture. The ingestible device may comprise chemicals configured toreact to provide a gas as the drive force generator.

The drive coupling may comprise a member selected from the groupconsisting of a piston and a membrane.

In some embodiments, when the restraining mechanism is in its firststate, the drive force generator does not apply an internal pressure tothe dispensable substance. In certain embodiments, when the restrainingmechanism is in its first state, the drive force generator applies aninternal pressure to the dispensable substance. The restrainingmechanism may have second state different from its first state, and,when the restraining mechanism is in its second state, the restrainingmechanism does not prevent the dispensable substance from beingdelivered out of the ingestible device. The restraining mechanism maycomprise a material selected from the group consisting of a degradablematerial, an erodible material and a dissolvable material. Therestraining mechanism may comprise an enteric material. The restrainingmechanism may comprise at least one member selected from the groupconsisting of a seal, a pin, a band, a dowel, a clasp, a clamp, aflange, and a rivet. The restraining mechanism may comprise a cap. Thecap may be located at a distal end of the ingestible device.

The housing may have a length of from about 20 mm to about 28 mm, fromabout 21 mm to about 27 mm, about 26 mm, or about 23.3 mm.

The housing may have a diameter of from about 7 mm to about 12 mm, fromabout 8 mm to about 11 mm, about 11 mm, about 9.9 mm, or about 8.5 mm.

The housing may comprise a wall having a wall thickness of from about0.5 mm to about 1 mm, from about 0.6 mm to about 0.9 mm, about 0.8 mm,about 0.7 mm.

The housing may comprise end regions that are spline-shaped or that arespherical.

The housing may comprise an end round of from about 1 mm to about 2 mm,about 1.5 mm, from about 4 mm to about 4.5 mm, about 4.25 mm, from about4.9 to about 5 mm, about 4.95 mm, from about 5.4 mm to about 5.6 mm, orabout 5.5 mm.

The housing may comprise an internal volume of from about 700 μL toabout 1700 μL, from about 750 μL to about 1650 μL, from about 800 μL toabout 1600 μL, or from about 850 μL to about 1550 μL.

The housing may comprise a fluid volume from about 50 μL to about 800μL, from about 100 μL to about 600 μL, or from about 200 μL to about 400μL.

The ingestible device may comprise a plurality of openings in thehousing configured to fluidly connect the dispensable substance to anenvironment outside the housing via the opening. The plurality ofopenings may comprise an even number of openings or an odd number ofopenings. The plurality of openings may comprise at least 25 openings,and/or at most 50 openings. Each opening may comprise a nozzle opening.

The opening may comprise a nozzle opening having a diameter from about 1mm to about 3 mm, at least about 1.5 mm, at least about 2 mm, and/or atmost about 2.5 mm.

The ingestible device may comprise a nozzle having a length of fromabout 1 mm to about 5 mm, from about 2 mm to about 5 mm, or from about 3mm to about 5 mm.

The dispensable substance may comprise a fluid. The dispensablesubstance may comprise a liquid. The dispensable substance may comprisea therapeutic agent. The dispensable substance may comprise a solution.The dispensable substance may comprise a suspension. The dispensablesubstance may have a viscosity of less than or equal to 10 cP, at leastabout 0.8 cP, at most about 8 cP, and/or or at most about 9 cP.

The ingestible device may be configured as a 00 capsule.

The ingestible device may be configured as a 000 capsule.

Third Group of General Aspects of the Disclosure

In a general aspect, the disclosure provides an ingestible device,comprising: a housing comprising first and second housing parts; and arestraining mechanism comprising a material having at least one propertyselected from the group consisting of selected being degradable, beingerodible and being dissolvable, wherein the ingestible device isconfigured so that: when the restraining mechanism is in a first state,the restraining mechanism has sufficient strength so that the first andsecond housing parts are connected such that a dispensable substance isstorable in the housing at a fluid pressure that is greater than 0 psig;and when the restraining mechanism is in a second state in which thematerial is at least partially degraded, eroded and/or dissolved, therestraining mechanism has reduced strength such that the first andsecond housing parts are sufficiently disconnected so that at least aportion of the dispensable substance leaves the ingestible device.

The fluid pressure may be greater than 5 psig. The fluid pressure may beat most about 50 psig. The fluid pressure may be from about 5 psig toabout 50 psig, from about 5 psig to about 30 psig, from about 5 psig toabout 20 psig, from about 8 psig to about 20 psig, or from about 10 psigto about 15 psig.

The second material may change from its first state to its second statein response to at least one condition selected from the group consistingof temperature, pH, presence of one or more enzymes, and time.

The restraining mechanism may comprise an enteric material. Therestraining mechanism may comprise at least one member selected from thegroup consisting of a seal, a pin, a band, a dowel, a clasp, a clamp, aflange, and a rivet.

The ingestible device may further comprise a drive force generatorconfigured to provide an internal pressure. The drive force generatormay comprise a gas. The gas may comprise a member selected from thegroup consisting of air, nitrogen, oxygen, carbon dioxide and a noblegas. The drive force generator may comprise a spring.

The ingestible device may further comprise a drive coupling configuredto transfer the internal pressure to the dispensable fluid. The drivecoupling may comprise a member selected from the group consisting of apiston and a membrane.

The internal pressure may be greater than 5 psig. The internal pressuremay be at most about 50 psig. The internal pressure may be from about 5psig to about 50 psig, from about 5 psig to about 30 psig, from about 5psig to about 20 psig, from about 8 psig to about 20 psig, or from about10 psig to about 15 psig.

The housing may have a length of from about 20 mm to about 28 mm, fromabout 21 mm to about 27 mm, about 26 mm, or about 23.3 mm.

The housing may have a diameter of from about 7 mm to about 12 mm, fromabout 8 mm to about 11 mm, about 11 mm, about 9.9 mm, or about 8.5 mm.

A ratio of the length of the housing to the width of the housing may befrom about 0.75 to about 4, from about 1 to about 3, or from about 1 toabout 2.

The ingestible device may be configured as a 00 capsule.

The ingestible device may be configured as a 000 capsule.

The housing may comprise a wall having a wall thickness of from about0.5 mm to about 1 mm, from about 0.6 mm to about 0.9 mm, about 0.8 mm,or about 0.7 mm.

The housing may comprise end regions that are spline-shaped or that arespherical.

The housing may comprise an end round of from about 1 mm to about 2 mm,about 1.5 mm, from about 4 mm to about 4.5 mm, about 4.25 mm, from about4.9 to about 5 mm, about 4.95 mm, from about 5.4 mm to about 5.6 mm, orabout 5.5 mm.

The ingestible device may be configured to deliver at least 50% of thedispensable substance into the lumen of the GI tract of a subject.

The ingestible device may further comprise the dispensable substance.The dispensable substance may comprise a fluid. The dispensablesubstance may comprise a liquid. The dispensable substance may comprisea therapeutic agent. The dispensable substance may comprise a solution.The dispensable substance may comprise a suspension. The dispensablesubstance may have a viscosity of less than or equal to 10 cP, at leastabout 0.8 cP, at most about 8 cP, or/or at most about 9 cP.

The ingestible device may be configured to deliver the dispensablesubstance to the lumen of the GI tract of a subject via topicaldelivery.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible to deliver a dispensable substance to the GI tract of thesubject.

In a general aspect, the disclosure provides a method, comprising: usingan ingestible device to deliver a dispensable substance to the lumen ofthe GI tract of a subject via topical delivery, wherein the ingestibledevice comprises: a housing; an opening in the housing configured tofluidly connect the dispensable substance to an environment outside thehousing via the opening; a drive force generator configured to provide aforce to the dispensable substance to deliver the dispensable substancethrough the opening; a drive force coupling configured to transfer theforce from the drive force generator to the dispensable substance; and arestraining mechanism having a first state in which the restrainingmechanism prevents the dispensable substance from being delivered out ofthe ingestible device.

The drive force generator may comprise a member selected from the groupconsisting of a spring, a gas cell, a compressed gas, and a liquid-gasmixture. The ingestible device may comprise chemicals configured toreact to provide a gas as the drive force generator.

The drive coupling may comprise a member selected from the groupconsisting of a piston and a membrane.

In some embodiments, when the restraining mechanism is in its firststate, the drive force generator does not apply an internal pressure tothe dispensable substance. In certain embodiments, when the restrainingmechanism is in its first state, the drive force generator applies aninternal pressure to the dispensable substance. The restrainingmechanism may have second state different from its first state, and,when the restraining mechanism is in its second state, the restrainingmechanism does not prevent the dispensable substance from beingdelivered out of the ingestible device. The restraining mechanism maycomprise a material selected from the group consisting of a degradablematerial, an erodible material and a dissolvable material. Therestraining mechanism may comprise an enteric material. The restrainingmechanism may comprise at least one member selected from the groupconsisting of a seal, a pin, a band, a dowel, a clasp, a clamp, aflange, and a rivet. The restraining mechanism may comprise a cap. Thecap may be located at a distal end of the ingestible device.

The housing may have a length of from about 20 mm to about 28 mm, fromabout 21 mm to about 27 mm, about 26 mm, or about 23.3 mm.

The housing may have a diameter of from about 7 mm to about 12 mm, fromabout 8 mm to about 11 mm, about 11 mm, about 9.9 mm, or of about 8.5mm.

A ratio of the length of the housing to the width of the housing may befrom about 0.75 to about 4, from about 1 to about 3, or from about 1 toabout 2.

The ingestible device may be configured as a 00 capsule.

The ingestible device may be configured as a 000 capsule.

The housing may comprise a wall having a wall thickness of from about0.5 mm to about 1 mm, from about 0.6 mm to about 0.9 mm, about 0.8 mm,or about 0.7 mm.

The housing may comprise end regions that are spline-shaped or that arespherical.

The housing may comprise an end round of from about 1 mm to about 2 mm,about 1.5 mm, from about 4 mm to about 4.5 mm, about 4.25 mm, from about4.9 to about 5 mm, about 4.95 mm, from about 5.4 mm to about 5.6 mm, orabout 5.5 mm.

The housing may have an internal volume of from about 700 μL to about1700 μL, from about 750 μL to about 1650 μL, from about 800 μL to about1600 μL, or from about 850 μL, to about 1550 μL.

The housing may have a fluid volume from about 50 μL to about 800 μL,from about 100 μL to about 600 μL, or from about 200 μL to about 400 μL.

The ingestible device may comprise a plurality of openings in thehousing configured to fluidly connect the dispensable substance to anenvironment outside the housing via the opening. The plurality ofopenings may comprise an even number of openings or an odd number ofopenings. The plurality of openings may comprise at least 25 openingsand/or at most 50 openings. Each opening may comprise a nozzle opening.

The opening may comprise a nozzle opening having a diameter from about 1mm to about 3 mm, at least about 1.5 mm, at least about 2 mm, and/or atmost about 2.5 mm.

The ingestible device may comprise a nozzle having a length of fromabout 1 mm to about 5 mm, from about 2 mm to about 5 mm, or from about 3mm to about 5 mm.

The dispensable substance may comprise a fluid. The dispensablesubstance may comprise a liquid. The dispensable substance may comprisea therapeutic agent. The dispensable substance may comprise a solution.The dispensable substance may comprise a suspension. The dispensablesubstance may have a viscosity of less than or equal to 10 cP, at leastabout 0.8 cP, at most about 8 cP, and/or at most about 9 cP.

General Aspects of the Disclosure Relating to Methods of Treating aMetabolic or Endocrine Disease or Condition Via Trans-EpithelialAdministration of a Dispensable Substance

In a general aspect, the disclosure provides a method of treating ametabolic or endocrine disease or condition in a subject in needthereof, the method including: trans-epithelially administering adispensable substance to the gastrointestinal (GI) tract of the subject,where the trans-epithelial administration includes: orally administeringan ingestible device containing the dispensable substance to thesubject, where the ingestible device is configured for trans-epithelialdelivery of the dispensable substance to the GI tract of the subject,and the dispensable substance contains a pharmaceutical formulationcontaining a therapeutically effective amount of a therapeutic agent;and releasing the dispensable substance from the ingestible device as atleast one jet to a desired location of the GI tract of the subject. Insome embodiments, the trans-epithelial administration directly deliversthe dispensable substance to the submucosa of the GI tract of thesubject. In some embodiments, the trans-epithelial administrationdirectly delivers at least a portion of the dispensable substance to themucosa of the GI tract of the subject. In further embodiments, thedirect delivery of the portion of the dispensable substance to themucosa of the GI tract of the subject further includes direct deliveryof at least some of the portion of the dispensable substance to thelamina propria.

In some embodiments of the method, the desired location of the GI tractis the small intestine. In some embodiments, the desired location of theGI tract is selected from the group consisting of duodenum, jejunum, andileum. In some embodiments, the desired location of the GI tract is theduodenum. In some embodiments, the desired location of the GI tract isthe jejunum. In some embodiments, the desired location of the GI tractis the ileum. In some embodiments, the desired location of the GI tractis the proximal small intestine. In some embodiments, the desiredlocation of the GI tract is the duodenum or jejunum. In someembodiments, the desired location of the GI tract is the distal smallintestine. In some embodiments, the desired location of the GI tract isthe jejunum or ileum.

In some embodiments of the method, the trans-epithelial administrationprovides systemic uptake of the therapeutic agent. In some embodiments,the systemic uptake of the therapeutic agent is at least about 10%, atleast about 15%, at least about 20%, at least about 25%, or at leastabout 30% relative to intravenous or subcutaneous administration of thesame amount of the therapeutic agent.

In some embodiments of the method, the trans-epithelial administrationprovides an area under the curve (AUC) of the therapeutic agent insystemic circulation over time (AUC_(TE)) that is at least about 10%, atleast about 15%, at least about 20%, at least about 25%, or at leastabout 30% of the AUC in systemic circulation over time provided byintravenous administration of the same amount of the therapeutic agent(AUC_(IV)).

In some embodiments of the method, the trans-epithelial administrationprovides an area under the curve (AUC) of the therapeutic agent insystemic circulation over time (AUC_(TE)) that is at least about 10%, atleast about 15%, at least about 20%, at least about 25%, or at leastabout 30% of the AUC in systemic circulation over time provided bysubcutaneous administration of the same amount of the therapeutic agent(AUC_(SC)).

In some embodiments of the method, the trans-epithelial administrationprovides a maximum plasma concentration (C_(max)) of the therapeuticagent in systemic circulation ((C_(max))_(TE)) that is at least about10%, at least about 15%, at least about 20%, at least about 25%, or atleast about 30% of the C_(max) in systemic circulation provided byintravenous administration of the same amount of the therapeutic agent((C_(max))_(IV)).

In some embodiments of the method, the trans-epithelial administrationprovides a maximum plasma concentration (C_(max)) of the therapeuticagent in systemic circulation ((C_(max))_(TE)) that is at least about10%, at least about 15%, at least about 20%, at least about 25%, or atleast about 30% of the C_(max) in systemic circulation provided bysubcutaneous administration of the same amount of the therapeutic agent((C_(max))_(SC)).

In some embodiments of the method, the metabolic or endocrine disease orcondition is responsive to treatment with the therapeutic agent.

In some embodiments of the method, the metabolic or endocrine disease orcondition is selected from the group consisting of diabetes, insulinresistance, hyperglycemia, hyperlipidemia, obesity, hepatic steatosis,hyperinsulinemia, obstructive sleep apnea, non-alcoholic fatty liverdisease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis,liver cirrhosis, hypertension, pulmonary artery hypertension, primarysclerosing cholangitis, hyperlipoproteinemia type I,hypercholesterolemia, a lipid metabolism disorder, atherosclerosis,lipodystrophy, acromegaly, myocardial infarction, and thromboembolism;and combinations thereof.

In some embodiments of the method, the metabolic or endocrine disease orcondition is diabetes. In some embodiments, the diabetes is type I ortype II diabetes. In some embodiments, the diabetes is selected from thegroup consisting of diabetes with Alzheimer's disease, diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with NAFLD, diabetes with NASH, diabetes with NAFLDand NASH, and diabetes with a cardiovascular disease. In someembodiments, the diabetes is diabetes with obesity.

In some embodiments of the method, the metabolic or endocrine disease orcondition is obesity.

In some embodiments of the method, the therapeutic agent is an insulin.In some embodiments, the insulin is selected from the group consistingof human insulin, insulin aspart, ultra-fast acting insulin aspart,insulin degludec, insulin detemir, insulin glargine, insulin glulisine,insulin lispro, and insulin tregopil; and biosimilars thereof.

In some embodiments of the method, the therapeutic agent is a glucagonreceptor agonist or a glucagon-like peptide-1 (GLP-1) receptor agonist.In some embodiments, the glucagon receptor agonist or the GLP-1 receptoragonist is glucagon; or a biosimilar thereof. In some embodiments, theglucagon receptor agonist or the GLP-1 receptor agonist is NN-9277; or abiosimilar thereof. In some embodiments, the glucagon receptor agonistor the GLP-1 receptor agonist is semaglutide; or a biosimilar thereof.In some embodiments, the glucagon receptor agonist or the GLP-1 receptoragonist is dulaglutide; or a biosimilar thereof. In some embodiments,the glucagon receptor agonist or the GLP-1 receptor agonist isalbiglutide; or a biosimilar thereof. In some embodiments, the glucagonreceptor agonist or the GLP-1 receptor agonist is exenatide; or abiosimilar thereof. In some embodiments, the glucagon receptor agonistor the GLP-1 receptor agonist is liraglutide; or a biosimilar thereof.In some embodiments, the glucagon receptor agonist or the GLP-1 receptoragonist is lixisenatide; or a biosimilar thereof. In some embodiments,the glucagon receptor agonist or the GLP-1 receptor agonist isNNC-0090-2746; or a biosimilar thereof.

In some embodiments of the method, the therapeutic agent is a peptide YYligand. In some embodiments, the peptide YY ligand is NN-9747, NN-9748or NN-9775; or a biosimilar thereof.

In some embodiments of the method, the therapeutic agent is an amylinanalog. In some embodiments, the amylin analog is AM-833; or abiosimilar thereof.

In some embodiments of the method, the therapeutic agent is a longacting growth differentiation factor 15.

In some embodiments of the method, the therapeutic agent isNNC0247-0829; or a biosimilar thereof.

In some embodiments of the method, the disease or condition is NAFLD,NASH, diabetes with NAFLD, diabetes with NASH, or diabetes with NAFLDand NASH. In some embodiments, where the disease or condition is NAFLD,NASH, diabetes with NAFLD, diabetes with NASH, or diabetes with NAFLDand NASH, the therapeutic agent is selected from the group consisting ofselonsertib, cenicriviroc, elafibranor, ocaliva, tropifexor, firocostat,cilofexor, aramchol, ARX618, BI 1467335, DS 102, EDP-305, emricasan,gemcabene, GR-MD-02, GRI-0621, GS-0976, GS-9674, IMM-124E,IONIS-DGAT2Rx, IVA-337, lipaglyn, LJN452, LLMB763, MGL-3196, MN-001,MSDC-0602K, NC101, NGM282, NGM313, NS-0200, ozempic, PF-05221304,PF-06835919, remogliflozin etabonate, SHP626, TVB-2640, VK2809, butanoicacid, CER209, evogliptin, DUR928, MK-4074, OPRX-106, PF06865571,PF06882961, PXS-5382A, RG-125, RYI-018, seladelpar, SGM-1019 andTVB-2640; and pharmaceutically acceptable salts thereof; and biosimilarsthereof. In some embodiments, the therapeutic agent is selected from thegroup consisting of selonsertib, cenicriviroc, elafibinor, ocaliva,tropifexor, firsocostat and cilofexor; and pharmaceutically acceptablesalts thereof.

In some embodiments of the method, the disease or condition ishypercholesterolemia, a lipid metabolism disorder, hyperlipidemia oratherosclerosis. In some embodiment, the hypercholesterolemia isfamilial hypercholesterolemia.

In some embodiments of the method, the therapeutic agent is a proproteinconvertase PC9 (PCSK9) inhibitor. In some embodiments, the PCSK9inhibitor is alirocumab or evolocumab; or a biosimilar thereof.

In some embodiments of the method, the therapeutic agent is selectedfrom aldesleukin, allogeneic human islets of langerhans, alogliptin,alpha-1 antitrypsin, anagliptin, benaglutide, berberine, bermekimab,bimagrumab, cibinetide, cotadutide, diabecell, diamyd, dutogliptinebenatide, efpeglenatide, evogliptin, FSI-965, gemigliptin, glutazumab,gosogliptin, hinsbet, LAI-287, linagliptin, mecasermin, omarigliptin,otelixizumab, pegapamodutide, peg-loxenatide, pramlintide acetate,prolastin, protrans, rexmyelocel-t, saxagliptin, sitagliptin,somatostatin, teneligliptin, teplizumab, tirzepatide, trelagliptin,vildagliptin, and combinations thereof; and pharmaceutically acceptablesalts thereof; and biosimilars thereof.

In some embodiments of the method, the therapeutic agent is selectedfrom the group consisting of bortezomib, fulvestrant, bendamustine,itolizumab, golimumab, canakinumab, trichuris suis ova, NNC-0385-0434,NGM-282, BMS-986036, and remestemcel-L; and pharmaceutically acceptablesalts thereof; and biosimilars thereof.

In some embodiments of the method, the therapeutic agent has a molecularweight of at least about 20 kDa, at least about 30 kDa, at least about40 kDa, at least about 50 kDa, or at least about 60 kDa; optionally, atleast about 20 kDa.

In some embodiments of the method, the pharmaceutical formulation is afluid. In some embodiments, the fluid is a liquid. In some embodiments,the pharmaceutical formulation is a solution or suspension.

In some embodiments of the method, the pharmaceutical formulation has aviscosity of less than or equal to 10 cP, at least about 0.8 cP, or atmost about 8 cP or at most about 9 cP.

In some embodiments of the method, the dispensable substance has a peakfluid pressure of about 200 psig to about 400 psig, at least about 250psig, at least about 275 psig, at least about 300 psig, at least about325 psig, about 275 psig to about 375 psig, about 275 psig to about 350psig, or about 275 psig to about 325 psig.

In some embodiments of the method, the at least one jet is a pluralityof jets. In some embodiments, each said jet released from the ingestibledevice has a diameter of about 0.1 mm to about 2 mm, about 0.1 mm toabout 1 mm, about 0.2 mm to about 0.8 mm, about 0.3 mm to about 0.5 mm,about 0.3 mm to about 0.4 mm, or about 0.35 mm.

In some embodiments of the method, each said jet has a mean jet velocityof about 20 m/s to about 30 m/s, about 20 m/s, about 21 m/s, about 22m/s, about 23 m/s, about 24 m/s, about 25 m/s, about 26 m/s, about 27m/s, about 28 m/s, about 29 m/s or 30 m/s.

In some embodiments of the method, the volume of the dispensablesubstance released from the ingestible device is about 50 microliters toabout 800 microliters, about 50 microliters to about 500 microliters,from about 100 microliters to about 450 microliters, from about 200microliters to about 400 microliters, from 250 microliters to about 400microliters, or from about 300 microliters to about 400 microliters.

In other general aspects of the method, the dispensable substance has apeak fluid pressure of about 275 psig to about 325 psig; and the atleast one jet is a plurality of jets, wherein each said jet releasedfrom the ingestible device has a diameter of about 0.1 mm to about 1 mm,about 0.3 mm to about 0.5 mm, or about 0.3 mm to about 0.4 mm. In someembodiments, each said jet has a mean jet velocity of from about 20 m/sto about 30 m/s or about 25 m/s to about 30 m/s. In some embodiments,the volume of the dispensable substance released from the ingestibledevice is from about 50 microliters to about 500 microliters, from about100 microliters to about 450 microliters, from about 200 microliters toabout 400 microliters, from 250 microliters to about 400 microliters, orfrom about 300 microliters to about 400 microliters. In someembodiments, the dispensable substance has a peak fluid pressure of atleast about 300 psig.

In other general aspects of the method, the ingestible device includes:a housing configured to contain the dispensable substance; and anopening in the housing configured to fluidly connect the dispensablesubstance to an environment outside the housing via the opening.

In further general aspects of the method, the opening in the housing isa plurality of openings, wherein each said opening includes a nozzle; orthe opening in the housing includes a plurality of nozzles; and eachsaid nozzle has an orifice to fluidly connect the dispensable substanceto the environment outside the housing and to release the dispensablesubstance from the ingestible device as the at least one jet.

In other general aspects of the method, the ingestible device furtherincludes: a drive force generator configured to provide a force to thedispensable substance to deliver the dispensable substance through theopening or the plurality of openings; and a drive force couplingconfigured to transfer the force from the drive force generator to thedispensable substance. In some aspects, the ingestible device furtherincludes: a restraining mechanism having a first state in which therestraining mechanism prevents the dispensable substance from beingdelivered out of the ingestible device; and a second state in which therestraining mechanism does not prevent the dispensable substance frombeing delivered out of the ingestible device.

In some embodiments of the method, the ingestible device is configuredas a 00-sized capsule. In some embodiments, the ingestible device isconfigured as a 000-sized capsule.

General Aspects of the Disclosure Relating to Methods of Treatment ViaTrans-Epithelial Administration of a Glucagon Receptor Agonist or GLP-1Receptor Agonist

In a general aspect, the disclosure provides, a method of treating adisease or condition in a subject in need thereof, the method including:trans-epithelially administering a dispensable substance to thegastrointestinal (GI) tract of the subject, where the trans-epithelialadministration includes: orally administering an ingestible devicecontaining the dispensable substance to the subject, where theingestible device is configured for trans-epithelial delivery of thedispensable substance to the GI tract of the subject, and thedispensable substance contains a pharmaceutical formulation containing atherapeutically effective amount of a glucagon receptor agonist or aglucagon-like peptide-1 (GLP-1) receptor agonist; and releasing thedispensable substance from the ingestible device as at least one jet toa desired location of the GI tract of the subject. In some embodiments,the trans-epithelial administration directly delivers the dispensablesubstance to the submucosa of the GI tract of the subject. In someembodiments, the trans-epithelial administration directly delivers atleast a portion of the dispensable substance to the mucosa of the GItract of the subject. In further embodiments, the direct delivery of theportion of the dispensable substance to the mucosa of the GI tract ofthe subject further comprises direct delivery of at least some of theportion of the dispensable substance to the lamina propria.

In some embodiments of the method, the desired location of the GI tractis the small intestine. In some embodiments, the desired location of theGI tract is selected from the group consisting of duodenum, jejunum, andileum. In some embodiments, the desired location of the GI tract is theduodenum. In some embodiments, the desired location of the GI tract isthe jejunum. In some embodiments, the desired location of the GI tractis the ileum. In some embodiments, the desired location of the GI tractis the proximal small intestine. In some embodiments, the desiredlocation of the GI tract is the duodenum or jejunum. In someembodiments, the desired location of the GI tract is the distal smallintestine. In some embodiments, the desired location of the GI tract isthe jejunum or ileum.

In some embodiments of the method, the trans-epithelial administrationprovides systemic uptake of the glucagon receptor agonist or GLP-1receptor agonist. In some embodiments, the systemic uptake of theglucagon receptor agonist or GLP-1 receptor agonist is at least about10%, at least about 15%, at least about 20%, at least about 25%, or atleast about 30% relative to intravenous or subcutaneous administrationof the same amount of the glucagon receptor agonist or GLP-1 receptoragonist, respectively.

In some embodiments of the method, the trans-epithelial administrationprovides an area under the curve (AUC) of the glucagon receptor agonistor GLP-1 receptor agonist in systemic circulation over time (AUC_(TE))that is at least about 10%, at least about 15%, at least about 20%, atleast about 25%, or at least about 30% of the AUC in systemiccirculation over time provided by intravenous administration of the sameamount of the glucagon receptor agonist or GLP-1 receptor agonist(AUC_(IV)), respectively.

In some embodiments of the method, the trans-epithelial administrationprovides an area under the curve (AUC) of the glucagon receptor agonistor GLP-1 receptor agonist in systemic circulation over time (AUC_(TE))that is at least about 10%, at least about 15%, at least about 20%, atleast about 25%, or at least about 30% of the AUC in systemiccirculation over time provided by subcutaneous administration of thesame amount of the glucagon receptor agonist or GLP-1 receptor agonist(AUC_(SC)), respectively.

In some embodiments of the method, the trans-epithelial administrationprovides a maximum plasma concentration (C_(max)) of the glucagonreceptor agonist or GLP-1 receptor agonist in systemic circulation((C_(max))_(TE)) that is at least about 10%, at least about 15%, atleast about 20%, at least about 25%, or at least about 30% of theC_(max) in systemic circulation provided by intravenous administrationof the same amount of the glucagon receptor agonist or GLP-1 receptoragonist ((C_(max))_(IV)), respectively.

In some embodiments of the method, the trans-epithelial administrationprovides a maximum plasma concentration (C_(max)) of the glucagonreceptor agonist or GLP-1 receptor agonist in systemic circulation((C_(max))_(TE)) that is at least about 10%, at least about 15%, atleast about 20%, at least about 25%, or at least about 30% of theC_(max) in systemic circulation provided by subcutaneous administrationof the same amount of the glucagon receptor agonist or GLP-1 receptoragonist ((C_(max))_(SC)), respectively.

In some embodiments of the method, the disease or condition isresponsive to treatment with the glucagon receptor agonist or GLP-1receptor agonist.

In some embodiments of the method, the disease or condition is ametabolic disorder or an endocrine disorder. In some embodiments, themetabolic disorder or endocrine disorder is diabetes. In someembodiments, the diabetes is selected from the group consisting ofdiabetes with Alzheimer's disease, diabetes with dementia, diabetes withAlzheimer's disease and dementia, diabetes with obesity, diabetes withnon-alcoholic fatty liver disease (NAFLD), diabetes with non-alcoholicsteatohepatitis (NASH), diabetes with NAFLD and NASH, and diabetes witha cardiovascular disease. In some embodiments, the disease or conditionis diabetes with obesity. In some embodiments, the diabetes is type 1 ortype 2 diabetes.

In some embodiments of the method, the disease or condition is a liverdisease or disorder. In some embodiments, the liver disease or disorderis compensated liver cirrhosis. In some embodiments, the disease orcondition is non-alcoholic steatohepatitis (NASH) or non-alcoholic fattyliver disease (NAFLD).

In some embodiments of the method, the disease or condition is a bingeeating disorder.

In some embodiments of the method, the disease or condition ishyperglycemia; optionally, the hyperglycemia is postprandialhyperglycemia.

In some embodiments of the method, the disease or condition is nicotinedependence.

In some embodiments of the method, the disease or condition is a centralnervous system (CNS) disorder. In some embodiments, the CNS disorder isAlzheimer's disease or Parkinson's disease.

In some embodiments of the method, the glucagon receptor agonist orGLP-1 receptor agonist is semaglutide; or a biosimilar thereof. In someembodiments, the glucagon receptor agonist or GLP-1 receptor agonist isdulaglutide; or a biosimilar thereof. In some embodiments, the glucagonreceptor agonist or GLP-1 receptor agonist is albiglutide; or abiosimilar thereof. In some embodiments, the glucagon receptor agonistor GLP-1 receptor agonist is exenatide; or a biosimilar thereof. In someembodiments, the glucagon receptor agonist or GLP-1 receptor agonist isliraglutide; or a biosimilar thereof. In some embodiments, the glucagonreceptor agonist or GLP-1 receptor agonist is lixisenatide; or abiosimilar thereof. In some embodiments, the glucagon receptor agonistor GLP-1 receptor agonist is NNC-0090-2746; or a biosimilar thereof. Insome embodiments, the glucagon receptor agonist or GLP-1 receptoragonist is glucagon; or a biosimilar thereof. In some embodiments, theglucagon receptor agonist or GLP-1 receptor agonist is NN-9277; or abiosimilar thereof. In some embodiments, the glucagon receptor agonistor GLP-1 receptor agonist is NN-9423; or a biosimilar thereof.

In some embodiments of the method, the glucagon receptor agonist orGLP-1 receptor agonist is TTP-054 or OWL883; and pharmaceuticallyacceptable salts thereof.

In some embodiments of the method, the glucagon receptor agonist orGLP-1 receptor agonist is compound 8, 9 or 10 having the structure:

Cpd R¹ R² R³ R⁴ R⁵ R⁶  8 H Me H Bn BIP BIP  9 H Me H BnBIP(2′-Et,4′-OMe) BIP(2′-Me) 10 Me Me Me 2-F-Bn BIP(2′-Et,4′-OMe) BIP(2′-Me);

wherein Bn is benzyl and BIP is biphenyl; or a pharmaceuticallyacceptable salt thereof.

In some embodiments of the method, the glucagon receptor agonist orGLP-1 receptor agonist is compound 3 or 4 having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the method, the glucagon receptor agonist orGLP-1 receptor agonist is a compound having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the method, the glucagon receptor agonist orGLP-1 receptor agonist is a compound having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the method, the glucagon receptor agonist orGLP-1 receptor agonist is compound 12, 13 or 14 having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the method, the glucagon receptor agonist orGLP-1 receptor agonist is a compound selected from the group consistingof:

and pharmaceutically acceptable salts thereof.

In some embodiments of the method, the glucagon receptor agonist orGLP-1 receptor agonist has a molecular weight of at least about 20 kDa,at least about 30 kDa, at least about 40 kDa, at least about 50 kDa, orat least about 60 kDa; optionally, at least about 20 kDa.

In some embodiments of the method, the pharmaceutical formulation is afluid. In some embodiments, the fluid is a liquid. In some embodiments,the pharmaceutical formulation is a solution or suspension.

In some embodiments of the method, the pharmaceutical formulation has aviscosity of less than or equal to 10 cP, at least about 0.8 cP, or atmost about 8 cP or at most about 9 cP.

In some embodiments of the method, the dispensable substance has a peakfluid pressure of about 200 psig to about 400 psig, at least about 250psig, at least about 275 psig, at least about 300 psig, at least about325 psig, about 275 psig to about 375 psig, about 275 psig to about 350psig, or about 275 psig to about 325 psig.

In some embodiments of the method, the at least one jet is a pluralityof jets. In some embodiments, each said jet released from the ingestibledevice has a diameter of about 0.1 mm to about 2 mm, about 0.1 mm toabout 1 mm, about 0.2 mm to about 0.8 mm, about 0.3 mm to about 0.5 mm,about 0.3 mm to about 0.4 mm, or about 0.35 mm.

In some embodiments of the method, each said jet has a mean jet velocityof from about 20 m/s to about 30 m/s, about 20 m/s, about 21 m/s, about22 m/s, about 23 m/s, about 24 m/s, about 25 m/s, about 26 m/s, about 27m/s, about 28 m/s, about 29 m/s or about 30 m/s.

In some embodiments of the method, the volume of the dispensablesubstance released from the ingestible device is from about 50microliters to about 800 microliters, about 50 microliters to about 500microliters, from about 100 microliters to about 450 microliters, fromabout 200 microliters to about 400 microliters, from 250 microliters toabout 400 microliters, or from about 300 microliters to about 400microliters.

In other general aspects of the method, the dispensable substance has apeak fluid pressure of about 275 psig to about 325 psig; and the atleast one jet is a plurality of jets, where each said jet released fromthe ingestible device has a diameter of about 0.1 mm to about 1 mm,about 0.3 mm to about 0.5 mm, or about 0.3 mm to about 0.4 mm. In someembodiments, each said jet has a mean jet velocity of about 20 m/s toabout 30 m/s or about 25 m/s to about 30 m/s. In some embodiments, thevolume of the dispensable substance released from the ingestible deviceis from about 50 microliters to about 500 microliters, from about 100microliters to about 450 microliters, from about 200 microliters toabout 400 microliters, from 250 microliters to about 400 microliters, orfrom about 300 microliters to about 400 microliters. In someembodiments, the dispensable substance has a peak fluid pressure of atleast about 300 psig.

In other general aspects of the method, the ingestible device contains:a housing configured to contain the dispensable substance; and anopening in the housing configured to fluidly connect the dispensablesubstance to an environment outside the housing via the opening. In someembodiments, the opening in the housing is a plurality of openings,wherein each said opening comprises a nozzle; or the opening in thehousing comprises a plurality of nozzles; and each said nozzle has anorifice to fluidly connect the dispensable substance to the environmentoutside the housing and to release the dispensable substance from theingestible device as the at least one jet. In some embodiments, theingestible device further includes: a drive force generator configuredto provide a force to the dispensable substance to deliver thedispensable substance through the opening or the plurality of openings;and a drive force coupling configured to transfer the force from thedrive force generator to the dispensable substance. In some embodiments,the ingestible device further includes: a restraining mechanism having afirst state in which the restraining mechanism prevents the dispensablesubstance from being delivered out of the ingestible device; and asecond state in which the restraining mechanism does not prevent thedispensable substance from being delivered out of the ingestible device.

In some embodiments of the method, the ingestible device is configuredas a 00-sized capsule. In some embodiments, the ingestible device isconfigured as a 000-sized capsule.

The details of one or more embodiments of the device and methods are setforth in the accompanying drawings and the description below. Otherfeatures and advantages will be apparent from the description anddrawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic cross section of the different regions of healthyintestinal tissue.

FIG. 1B is a schematic cross section corresponding to FIG. 1A but fordiseased intestinal tissue.

FIG. 2 is a cross section of an ingestible device.

FIG. 3 is a cross section of an ingestible device.

FIG. 4A shows the exterior surface of an ingestible device.

FIG. 4B is a top view cross section of the ingestible device in an openposition.

FIG. 4C is a front view cross section of the ingestible device in theopen position.

FIG. 5A is a top view cross section of the ingestible device in theclosed position.

FIG. 5B is a front view cross section of the ingestible device of in theclosed position.

FIGS. 6A-6L shows exemplary nozzle cross sections for the ingestibledevice.

FIG. 7 shows an exemplary histology slide resulting from a bolus oftherapeutic agent in situ.

FIG. 8 shows an exemplary process flow chart for use of an ingestibledevice in which pressure is applied to the dispensable substance beforethe subject swallows the ingestible device.

FIG. 9A shows an ingestible device.

FIG. 9B shows certain elements of the ingestible device of FIG. 9A.

FIG. 10A shows an ingestible device.

FIG. 10B shows an exploded view of the ingestible device of FIG. 10A.

FIG. 10C shows aspects of steps in assembling the ingestible device ofFIG. 10A.

FIG. 10D shows an ingestible device with aspects similar to those shownin FIG. 10A.

FIG. 10E shows an ingestible device with aspects similar to those shownin FIG. 10A.

FIG. 11 shows an ingestible device.

FIG. 12 shows an ingestible device.

FIG. 13 shows an ingestible device.

FIG. 14 shows an ingestible device.

FIG. 15A shows an ingestible device.

FIG. 15B shows an exploded view of the ingestible device of FIG. 15A.

FIG. 15C shows aspects of steps in assembling the ingestible device ofFIG. 15A.

FIG. 16 shows an exemplary process flow chart for use of an ingestibledevice in which pressure is not applied to the dispensable substancebefore the subject swallows the ingestible device.

FIG. 17 shows an ingestible device.

FIG. 18 shows an ingestible device.

FIG. 19A shows an ingestible device.

FIG. 19B shows an exploded view of the ingestible device of FIG. 19A.

FIG. 19C shows aspects of steps in assembling the ingestible device ofFIG. 19A.

FIG. 19D shows an ingestible device with aspects similar to those shownin FIG. 19A.

FIG. 19E shows an ingestible device with aspects similar to those shownin FIG. 19A.

FIG. 19F shows an ingestible device with aspects similar to those shownin FIG. 19A.

FIG. 19G shows an ingestible device with aspects similar to those shownin FIG. 19A.

FIG. 19H shows an ingestible device with aspects similar to those shownin FIG. 19A.

FIGS. 19I and 19J show aspects of states of an ingestible device.

FIGS. 19K and 19L show aspects of states of an ingestible device.

FIGS. 20A and 20B show an ingestible device.

FIGS. 21A and 21B show an ingestible device.

FIG. 22 shows an ingestible device.

FIG. 23A shows an ingestible device.

FIG. 23B shows an exploded view of the device of FIG. 23A.

FIG. 24 shows an ingestible device.

FIG. 25 shows an ingestible device.

FIG. 26A shows an ingestible device.

FIG. 26B shows an exploded view of the device of FIG. 26A.

FIG. 26C shows aspects of states of the ingestible device of FIG. 26A.

FIG. 27 shows an ingestible device.

FIG. 28A shows an ingestible device.

FIG. 28B shows an exploded view of the device of FIG. 28A.

FIG. 29A shows an ingestible device.

FIG. 29B shows an exploded view of the device of FIG. 29A.

FIG. 29C shows aspects of states of the ingestible device of FIG. 29A.

FIG. 30 shows an ingestible device.

FIG. 31A shows an ingestible device.

FIG. 31B shows aspects of states of the ingestible device of FIG. 31A.

FIG. 32 shows an ingestible device.

FIGS. 33-37 are graphs showing modelling results for ingestible deviceshaving two nozzles.

FIGS. 38-47 are graphs showing modelling results for ingestible deviceshaving two or four nozzles.

FIG. 48 shows blood insulin levels in swine after subcutaneous (SC)administration.

FIG. 49 shows blood insulin levels in swine after jejunum (IJ)administration.

FIG. 50 shows blood insulin levels and dextrose infusion rates in the SCadministration group.

FIG. 51 shows blood insulin levels and dextrose infusion rates in the IJadministration group.

FIG. 52 shows adalimumab concentration in swine plasma over 10 daysafter: ID administration via the endoscopically placed ingestible devicehaving an internal pressure of 220 psig, 270 psig or 320 psig; SCadministration; and IV administration.

FIGS. 53A-53C show dulaglutide concentration in blood over time after:ID administration via the endoscopically placed ingestible device aninternal pressure of 320 psig (FIG. 53A); SC administration (FIG. 53B);and IV administration (FIG. 53C).

FIG. 54 shows the plasma concentration of dulaglutide over time via IDadministration relative to IV or SC administration.

FIGS. 55A-55B show the plasma concentration of adalimumab over time inindividual animals. FIG. 55A represents animals treated with adalimumabafter ID administration via the endoscopically placed ingestible devicehaving 4 nozzles and an internal pressure of 320 psig. FIG. 55Brepresents animals treated with adalimumab after ID administration viathe endoscopically placed ingestible device having 4 nozzles and aninternal pressure of 350 psig.

FIG. 56 shows the mean plasma concentration of adalimumab (ng/mL±SEM)over time (0-240 hours) after ID administration via the endoscopicallyplaced ingestible device having: 4 nozzles and an internal pressure of320 psig (Group 1); 4 nozzles and an internal pressure of 350 psig(Group 2); 2 nozzles and an internal pressure of 320 psig.

FIGS. 57A-57B illustrate the general principle of a competitiveinhibition assay. FIG. 57A shows binding of anti-TNFα to the TNFαreceptor without drug, where uninhibited binding brings the Donor andAcceptor beads into close proximity for singlet oxygen transferdetection. FIG. 57B shows binding of anti-TNFα to TNFα that is inhibitedby drug binding to TNFα, thus preventing binding to anti-TNFα antibodiesand proximity oxygen singlet transfer detection.

FIGS. 58A-58B are dose response curves of adalimumab binding toTNF-alpha. FIG. 58A shows the dose response curve after 10,000 pg/mL ofadalimumab was dispensed into collection tubes under various conditionsas described in Example 8. FIG. 58B is an enlarged view of a section ofthe graph shown in FIG. 58A.

FIG. 59 is a flow chart of the experimental design.

FIG. 60 shows the assay principle of negative control (NC) production.

FIG. 61 shows the results of a gel analysis.

FIGS. 62A-62B show mean plasma (FIG. 62A) and colon tissue (FIG. 62B)concentrations of tofacitinib (free base) over a 24-hour periodpost-treatment with tofacitinib citrate or vehicle in a DSS-inducedcolitis mouse model. Dashed lines indicate in vitro IC₅₀ values forJAK1/3, JAK1/2 and JAK2/2 in whole blood. Error bars represent standarddeviation.

FIGS. 63A-63C show plasma (FIG. 63A), colon content (FIG. 63B) and colontissue (FIG. 63C) tofacitinib exposure (AUC_(0-24 h)) after treatmentwith vehicle or tofacitinib citrate via per oral (PO) or intracecal (IC)administration in a DSS-induced colitis mouse model.

FIGS. 64A-64B show IL-6 concentrations in colon tissue over a 24-hourperiod post-treatment with vehicle or tofacitinib citrate via per oral(PO) or intracecal (IC) administration in a DSS-induced colitis mousemodel on Study Day 12. FIG. 64A shows IL-6 concentrations in colontissue at various timepoints on Study Day 12. FIG. 64B shows therelationship between tofacitinib concentration in colon tissue (openshapes and dotted lines; right y-axis) and % IL-6 in colon tissue aftertreatment with tofacitinib citrate, normalized to DSS vehicle control(Group 2) (solid shapes and solid lines; left y-axis).

FIG. 65 is a graph showing the Disease Activity Index (DAI) of naïvemice (Group 1), mice administered vehicle only both intraperitoneally(IP) and intra-cecally (IC) (Group 2), mice administered an anti-TNFαantibody IP and vehicle IC (Group 7), and mice administered an anti-TNFαantibody IC and vehicle IP (Group 8) at Day 28 and Day 42 of the studydescribed in Example 10.

FIG. 66 is a set of graphs showing the colonic tissue concentration ofTNFα, IL-17A, IL-4, and IL-22 in mice administered vehicle only both IPand IC (Group 2), mice administered IgG control antibody IP and vehicleIC (Group 3), mice administered IgG control IC and vehicle IP (Group 4),mice administered anti-TNFα antibody IP and vehicle IC (Group 7), andmice administered anti-TNFα antibody IC and vehicle IP (Group 8) at Day42 of the study described in Example 10.

FIG. 67 is a graph showing the Disease Activity Index (DAI) of naïvemice (Group 1), mice administered vehicle only both IP and IC (Group 2),mice administered an anti-IL12 p40 antibody IP and vehicle IC (Group 5),and mice an anti-IL12 p40 antibody IC and vehicle IP (Group 6) at Day 28and Day 42 of the study described in Example 10.

FIG. 68 is a set of graphs showing the colonic tissue concentration ofIFN-gamma, IL-6, IL-17A, TNFα, IL-22, and IL-1b in naïve mice (Group 1),mice administered vehicle only both IP and IC (Group 2), miceadministered anti-IL12 p40 antibody IP and vehicle IC (Group 5), andmice administered anti-IL12 p40 antibody IC and vehicle IP (Group 8) atDay 42 of the study described in Example 10.

FIGS. 69A-69B show body weight changes (mean % SEM). FIG. 69A shows theinfluence of anti-TNF-alpha; FIG. 69B shows the influence ofanti-IL12p40. The AUC was calculated using the trapezoidal rule and isshown in the figure inset. Differences in body weight loss werecalculated as AUC for individual mouse from Days 0 to 42. Two-tailedMann-Whitney U-Test; p<0.05*; p<0.01**; p<0.005***, n=5-9.

FIG. 70 shows total histopathology score (mean %±SEM) in ileum, proximalcolon and distal colon tissues after targeted IC anti-TNF-alphatreatment compared with vehicle and IP treatment groups. Pair-wisecomparisons by two-tailed Mann-Whitney U-Test for treatment effects;p<0.05*.

FIGS. 71A-71D show mean lymphocyte counts from luminal to externalsubmucosa of proximal colon and represented images of H&E stains and IHCstains of the proximal colon. FIG. 71A shows the mean lymphocyte countfrom most inner lumen to submucosal of the proximal colon in groupstreated with Vehicle controls, anti-TNFα (IP) and anti-TNFα (IC), Groupmean+/−SEM. Kruskal-Wallis Test with Dunn's multiple comparison fortreatment effects; p<0.05*. FIG. 71B is a representative image of H&Estain of proximal colon in proximal colon of anti-TNFα (IC) group. Anintraepithelial lymphocyte (white arrowhead), example lamina propriallymphocytes (black arrowheads), and the tunica muscularis externa (TME)are indicate. FIGS. 71C and 71D are representative images of IHC stainof CD4 marker for lymphocytes in proximal colon of anti-TNFα (IC) (FIG.71C) or anti-TNFα (IP) (FIG. 71D) group.

FIGS. 72A-72C show semaglutide concentration in blood over time after:ID administration via the endoscopically placed ingestible jet deliverydevice (FIG. 72A); SC administration (FIG. 72B); and IV administration(FIG. 72C).

FIG. 73 shows the (AUC)_(T0-T10 d) observed after administration ofadalimumab intraduodenally (ID) via an ingestible jet delivery devicehaving an internal pressure of 320 psig (Example 5, Group 3), ID via anendoscopic injection needle (Example 12), subcutaneously (Example 5,Group 4) and intravenously (Example 5, Group 5).

DETAILED DESCRIPTION Definitions

“Ingestible,” as used herein in reference to the device, means that thedevice can be swallowed whole.

An “antibody” is an immunoglobulin molecule capable of specific bindingto a target, such as a carbohydrate, polynucleotide, lipid, polypeptide,etc., through at least one antigen recognition site, located in thevariable region of the immunoglobulin molecule. The terms “antibody” and“immunoglobulin” are used interchangeably in the broadest sense. As usedherein, the terms encompass monoclonal antibodies (for example, fulllength or intact monoclonal antibodies), polyclonal antibodies (forexample, full length or intact polyclonal antibodies), and fragmentsthereof (such as Fab, Fab′, F(ab′)2, Fv), single chain (ScFv) and domainantibodies), fusion proteins including an antibody portion, multivalentantibodies, multispecific antibodies (e.g., bispecific, trispecific,etc. antibodies so long as they exhibit the desired biologicalactivity), and any other modified configuration of the immunoglobulinmolecule that includes an antigen recognition site. An antibody can behuman, humanized and/or affinity matured.

The term antibody includes antibody fragments (e.g., antigen-bindingfragments) such as an Fv fragment, a Fab fragment, a F(ab′)2 fragment,and a Fab′ fragment. “Antibody fragments” comprise only a portion of anintact antibody, where in certain embodiments, the portion retains atleast one, and typically most or all, of the functions normallyassociated with that portion when present in an intact antibody. In oneembodiment, an antibody fragment comprises an antigen binding site ofthe intact antibody and thus retains the ability to bind antigen. Inanother embodiment, an antibody fragment, for example one that comprisesthe Fc region, retains at least one of the biological functions normallyassociated with the Fc region when present in an intact antibody, suchas FcRn binding, antibody half-life modulation, ADCC function andcomplement binding. In one embodiment, an antibody fragment is amonovalent antibody that has an in vivo half-life substantially similarto an intact antibody. For example, such an antibody fragment maycomprise an antigen binding arm linked to an Fc sequence capable ofconferring in vivo stability to the fragment. Additional examples ofantigen-binding fragments include an antigen-binding fragment of an IgG(e.g., an antigen-binding fragment of IgG1, IgG2, IgG3, or IgG4) (e.g.,an antigen-binding fragment of a human or humanized IgG, e.g., human orhumanized IgG1, IgG2, IgG3, or IgG4); an antigen-binding fragment of anIgA (e.g., an antigen-binding fragment of IgA1 or IgA2) (e.g., anantigen-binding fragment of a human or humanized IgA, e.g., a human orhumanized IgA1 or IgA2); an antigen-binding fragment of an IgD (e.g., anantigen-binding fragment of a human or humanized IgD); anantigen-binding fragment of an IgE (e.g., an antigen-binding fragment ofa human or humanized IgE); or an antigen-binding fragment of an IgM(e.g., an antigen-binding fragment of a human or humanized IgM). Anantibody includes an antibody of any class, such as IgG, IgA, or IgM (orsub-class thereof), and the antibody need not be of any particularclass. Depending on the antibody amino acid sequence of the constantdomain of its heavy chains, immunoglobulins can be assigned to differentclasses. There are five major classes of immunoglobulins: IgA, IgD, IgE,IgG, and IgM, and several of these may be further divided intosubclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. Theheavy-chain constant domains that correspond to the different classes ofimmunoglobulins are called alpha, delta, epsilon, gamma, and mu,respectively. The subunit structures and three-dimensionalconfigurations of different classes of immunoglobulins are well known.

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations that may be present inminor amounts. Monoclonal antibodies are highly specific, being directedagainst a single antigen or antigenic site. Furthermore, in contrast topolyclonal antibody preparations that typically include differentantibodies directed against different determinants (epitopes), eachmonoclonal antibody is directed against a single determinant on theantigen. The modifier “monoclonal” indicates the character of theantibody as being obtained from a substantially homogeneous populationof antibodies, and is not to be construed as requiring production of theantibody by any particular method. For example, the monoclonalantibodies to be used in accordance with the present disclosure may bemade by the hybridoma method first described by Kohler and Milstein,1975, Nature 256:495, or may be made by recombinant DNA methods such asdescribed in U.S. Pat. No. 4,816,567. The monoclonal antibodies may alsobe isolated from phage libraries generated using the techniquesdescribed in McCafferty et al., 1990, Nature 348:552-554, for example.

The monoclonal antibodies herein specifically include “chimeric”antibodies in which a portion of the heavy and/or light chain isidentical with or homologous to corresponding sequences in antibodiesderived from a particular species or belonging to a particular antibodyclass or subclass, while the remainder of the chain(s) is identical withor homologous to corresponding sequences in antibodies derived fromanother species or belonging to another antibody class or subclass, aswell as fragments of such antibodies, so long as they exhibit thedesired biological activity (U.S. Pat. No. 4,816,567; and Morrison etal, Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)).

A “variable region” of an antibody refers to the variable region of theantibody light chain or the variable region of the antibody heavy chain,either alone or in combination. As known in the art, the variableregions of the heavy and light chain each consist of four frameworkregions (FR) connected by three complementarity determining regions(CDRs) that contain hypervariable regions. The CDRs in each chain areheld together in close proximity by the FRs and, with the CDRs from theother chain, contribute to the formation of the antigen-binding site ofantibodies. There are at least two techniques for determining CDRs: (1)an approach based on cross-species sequence variability (i.e., Kabat etal., Sequences of Proteins of Immunological Interest, (5th ed., 1991,National Institutes of Health, Bethesda Md.)); and (2) an approach basedon crystallographic studies of antigen-antibody complexes (Al-Lazikaniet al., 1997, J. Molec. Biol. 273:927-948). As used herein, a CDR mayrefer to CDRs defined by either approach or by a combination of bothapproaches.

As known in the art, a “constant region” of an antibody refers to theconstant region of the antibody light chain or the constant region ofthe antibody heavy chain, either alone or in combination.

“Bioavailability,” as used herein, may be reported based on the ratio ofthe area under a curve (AUC) of the therapeutic agent concentration insystemic circulation versus time that is achieved when the drug isadministered by another form of administration (e.g., trans-epithelialadministration [hereinafter, AUC)_(TE)] or topical administration[hereinafter, AUC)_(TOP)], respectively) versus the AUC of thetherapeutic agent concentration in systemic circulation versus time thatis achieved when the same amount of the drug is administeredintravenously [hereinafter, (AUC)_(IV)], or subcutaneously [hereinafter,(AUC)_(SC)], expressed as a percentage. In some aspects, especially whenthe pharmacokinetic data are derived from more than one subject, the AUCis a mean AUC. In some embodiments, the mean is a geometric mean. Inother aspects, as used herein, drug exposure may be reported based on adifferent pharmacokinetic parameter. For example, drug exposure may bereported as a ratio of maximum therapeutic agent concentration (C_(max))in systemic circulation that is achieved when the drug is administeredby another form of administration (e.g., trans-epithelial administration[hereinafter, (C_(max))_(TE)] or topical administration [hereinafter,(C_(max))_(TOP)]), versus the C_(max) of the therapeutic agentconcentration in systemic circulation that is achieved when the sameamount of the drug is administered intravenously [hereinafter,(C_(max))_(IV)], or subcutaneously [hereinafter, (C_(max))_(SC)],expressed as a percentage.

As used herein, “non-oral,” when used in reference to a therapeuticsuitable for use with the devices and methods of the present disclosure,refers to a therapeutic or active agent that has poor bioavailabilityand/or is not administered by an oral route of administration.

The term “chemokine/chemokine receptor inhibitors” refers to an agentwhich decreases the ability of a chemokine to bind to its receptor,where the chemokine is one of CXCL10 (IL-10), CCL11, or an ELRchemokine, or the chemokine receptor is CCR2 or CCR9.

“Effective amount” as used herein refers to an amount of therapeuticagent that offers beneficial response to a patient receiving thetreatment. For example, an effective amount may be a Human EquivalentDose (HED). The phrase “therapeutically effective amount,” as usedherein, refers to the amount of the therapeutic agent that is effectivefor producing a desired therapeutic effect. In some embodiments, atherapeutically effective amount treats or prevents a disease orcondition disclosed herein.

“Mucosa-associated lymphoid tissue” or “MALT” used herein refers to adiffuse system of small concentrations of lymphoid tissue found invarious submucosal membrane sites of the body, such as thegastrointestinal tract, oral passage, nasopharyngeal tract, thyroid,breast, lung, salivary glands, eye, and skin.

“Gut-associated lymphoid tissue” or “GALT” as used herein refers to apart of the broader MALT and includes, e.g., Peyer's patches, mesenerticlymph nodes, and isolated lymphoid follicles/intestinal lymphoidaggregates.

“Peyer's patches” as used herein refers to aggregated lymphoid modulesorganized into follicles and are important part of GALT. Peyer's patchesare mainly present in the distal jejunum and the ileum.

“Mesenteric lymph nodes” as used herein refers to part of the paraaorticlymph node system that is a group of lymph nodes that lie between thelayers of the mesentery and drain the gut tissues and deliver lymph tothe thoracic duct. Mesenteric lymph nodes include the “superiormesenteric lymph nodes” which receive afferents from the jejunum, ileum,cecum, and the ascending and parts of the transverse colon. Mesentericlymph nodes also include “inferior mesenteric lymph nodes” which arelymph nodes present throughout the hindgut. The hindgut, e.g., includesthe distal third of the transverse colon and the splenic flexure, thedescending colon, sigmoid colon, and the rectum. The lymph nodes draininto the superior mesenteric lymph nodes and ultimately to the preaorticlymph nodes.

“Paraaortic lymph nodes” as used herein refers to a group of mesentericlymph nodes that lie in front of the lumbar vertebrae near the aorta.The paraaortic lymph nodes receive drainage from the gastrointestinaltract and the abdominal organs. Paraaortic lymph nodes include, e.g.,retroaortic lymph nodes, lateral aortic lymph nodes, preaortic lymphnodes (e.g., Celiac, gastric, hepatic, and splenic lymph nodes),superior mesenteric lymph nodes (e.g., mesenteric, ileocolic, andmesocolic lymph nodes), and inferior mesenteric lymph nodes (e.g.,pararectal lymph nodes).

A drug's international nonproprietary name (INN), as used herein, is tobe interpreted as including generic, bioequivalent and biosimilarversions of that drug, including but not limited to any drug that hasreceived abbreviated regulatory approval by reference to an earlierregulatory approval of that drug. Additionally, all drugs disclosedherein optionally include the pharmaceutically acceptable salts andsolvates of the drugs thereof, and the biosimilars thereof, and/orglycosylation variants thereof, in the case of biologics such asantibodies, unless expressly indicated otherwise.

As used herein, each listed small molecule, peptide or nucleic acidagent optionally includes a pharmaceutically acceptable salt thereof,whether or not such a form is expressly indicated. Each listed antibodyagent optionally includes a biosimilar thereof, or a glycosylationvariant thereof, whether or not such a biosimilar or glycosylationvariant is expressly indicated.

“Dispensable” as used herein with reference to any substance, refers toany substance that may be released from an ingestible device asdisclosed herein, or from a component of the device such as a reservoir.For example, a dispensable substance may be a therapeutic agent asdisclosed herein, and/or a formulation that includes a therapeutic agentas disclosed herein. A dispensable substance may be a fluid, such as aliquid, a suspension or a semi-solid. For example, a dispensablesubstance can be a liquid in the form of a solution, such as an aqueoussolution. In some embodiments, when disposed in an ingestible device, asubstance is a non-fluid, such as a solid. In such embodiments, thesubstance may be converted to a fluid prior to being delivered from theingestible device. In some embodiments, the therapeutic agent is a smallmolecule. In other embodiments, the therapeutic agent is a largemolecule, such as a biologic drug. Nonlimiting examples of biologicdrugs include antibodies (including monoclonal antibodies), proteins(including fusion proteins), peptides (including cyclic peptides), cells(including stem cells), and nucleic acids (including inhibitory nucleicacids, antisense nucleic acids, siRNA, ribozymes). In some embodiments,the dispensable substance is a pharmaceutical formulation comprising atherapeutic agent and a liquid carrier. In some embodiments, thepharmaceutical formulation comprising the therapeutic agent and theliquid carrier is a solution formulation. In other embodiments, thepharmaceutical formulation comprising the therapeutic agent and theliquid carrier is a suspension formulation, or an emulsion formulation.In some embodiments, a dispensable substance delivered as describedherein is particularly well-suited for treatment of diseases andconditions of the endoderm, for example, it may be more efficacious ingut-associated lymphoid tissue (GALT) or the hepatic system as comparedto subcutaneous or intravenous administration. In general, the viscosityof a dispensable substance can be selected as appropriate. In someembodiments, the dispensable substance has a viscosity of at least about0.5 centiPoise (cP) (e.g., at least about 0.8 cP, at least about 1 cP,at least about 2 cP, at least about 3 cP, at least about 4 cP, at leastabout 5 cP) and/or at most about 10 cP (e.g., at most about 9 cP, atmost about 8 cP, at most about 7 cP). In certain embodiments thedispensable substance has a viscosity of from about 0.5 cP to about 10cP (e.g., from about 0.8 cP to about 9 cP, from about 0.8 cP to about 8cP).

As used herein, the term “enteric” refers a material that permitstransition to a desired location in the GI tract (e.g., through thestomach to the intestine) before being dissolved/degraded/eroded due toexposure of certain conditions (e.g., pH, temperature, enzymes) of theGI tract. An enteric material may prevent a drug from degradation bygastric fluid and enzymes. In some embodiments, an enteric composition(e.g., when formed as a coating on the housing of an ingestible device)is selected from mixtures of fats and fatty acids; shellac and shellacderivatives; and cellulose acetate phthalates. An enteric material canbe an enteric polymer. In some embodiments, an enteric polymer canremain insoluble in the stomach, but dissolve at the higher pH of theintestine (e.g., small intestine or large intestine), and are used todeliver drugs to the intestine. Examples include Colorcon's OpadryEnteric 91 series Polyvinyl Acetate Phthalate, Opadry Enteric 94 seriesMethacrylic Acid, Opadry Enteric 95 series Methacrylic Acid, SuretericPVAP (Polyvinyl Acetate Phthalate), Nutrateric Ethylcellulose EvonikAcryl-EZE (Colorcon & Evonik collaboration—Eudragit L 100-55 MixtureMethacrylic copolymers); Evonik's Eudragit L 100-55 Methacryliccopolymers, Eudragit L 30 D-55 Methacrylic copolymers (30%), EudragitL100 Methacrylic copolymers, EudragitL 12,5 Methacrylic copolymers(12.5%), Eudragit S 100 Methacrylic copolymers, Eudragit S 12,5Methacrylic copolymers (12.5%), Eudragit FS 30 D Methacrylic copolymers(30%); Kerry's SheffCoat ENT Cellulose Acetate Phthalate, Acrylatecopolymer, HPMC-P; Eastman's C-A-P NF Cellulose Acetate Phthalate;Sensient's PROTECT™ ENTERIC Shellac & Sodium Alginate. In certainembodiments, an enteric material dissolves in the small intestine and issuitable for small intestine release. Examples of such enteric materialsinclude, but are not limited to, cellulose derivatives, e.g., celluloseacetate phthalate, hydroxypropylmethylcellulose phthalate (HPMCP),hydroxypropylmethylcellulose acetate succinate (HPMCAS) and RL100 (e.g.,HP-55), malic acid-propane 1,2-diol, polyvinyl acetate phthalate,anionic polymers of methacrylic acid and methyl methacrylate,hydroxypropylcellulose acetate phthalate, polyvinyl acetate phthalate,methacrylate-methacrylic acid copolymers, styrol, maleic acidcopolymers, shellac, and others. Another suitable enteric material is awater emulsion of ethylacrylate methylacrylic acid copolymer, orhydroxypropyl methyl cellulose acetate succinate (HPMAS). (See, e.g.,U.S. Pat. No. 5,591,433). In some embodiments, an enteric materialdissolves in the large intestine and is suitable for colonic release.Enteric materials suitable for large intestine (e.g., colonic) releaseare known to one of skill in the art. In some embodiments, degradationof the coating is microbially triggered, e.g., the bacteria in the colonenzymatically trigger degradation of the coating (see, e.g., Archana etal., Int. J. Pharm. Sci. Res. (2016) 1(5):40-47; and Sethi et al., Int.J. Pharm. Sci. Res. (2012) 3(9):2989-3000). In some embodiments, thecoating is a pH-dependent polymer that is insoluble at low pH butbecomes increasingly soluble as pH increases. In some embodiments, thecoating is a polymethacrylates with a pH-dependent dissolution thresholdof about pH 6.0 to about 7.0. Examples of suitable enteric materialsinclude, but are not limited to, chitosan, alginates (e.g., as calciumsalts), Eudragit® L (e.g., Eudragit® 100), Eudragit® S (e.g., Eudragit®S 100), Eudragit® L (e.g., Eudragit® L-30D), Eudragit® FS (e.g.,Eudragit® FS 30D), hydroxypropylmethylcellulose phthalate 50,hydroxypropylmethylcellulose phthalate 55, and cellulose acetatetrimellate. In some embodiments, an enteric material is a materialdescribed in U.S. Pat. No. 10,226,430; Sethi et al., Int. J. Pharm. Sci.Res. (2012) 3(9):2989-3000; or Archana et al., Int. J. Pharm. Sci. Res.(2016) 1(5):40-47, each of which are herein incorporated by reference intheir entireties. In some embodiments, the colon-specific degradation ofan enteric material can be based on the presence of microorganisms thatreside only in the colon, more particularly, biodegradable enzymesproduced by these microorganisms. In general, such microorganisms areanaerobic bacteria, e.g., Bacteroides, Bifidobacteria, Enterobacteria,Eubacteria, Clostridia, Enterococci, and Ruminococcus, etc. These microfloras fulfill their energy needs by fermenting various types ofsubstrates that have been left undigested in the small intestine, e.g.,polysaccharides, di- and tri-saccharides, etc. These polymers are stablein the environments of the stomach and small intestine. On reaching thecolon, the polymers undergo degradation by the enzyme or break down ofthe polymer backbone leads to a subsequent reduction in their molecularweight and thereby loss of the mechanical strength.

The term “jet,” as used herein, refers to a collimated stream of fluid,e.g., liquid or suspension, that is stable without breaking up into aspray. A jet may be formed by forcing the fluid, e.g., liquid orsuspension, through an opening in an ingestible device. Generally, a jetmaintains a stable form and is capable of achieving its intended purposeby maintaining appropriate properties (e.g., to penetrate a surface),such as its diameter and/or velocity.

As used herein, “jet diameter” is the cross-sectional diameter of a jetat a given location.

As used herein, “average jet diameter” refers to the averagecross-sectional diameter of a jet between the location where the jet isformed (e.g., a nozzle opening through which the dispensable substanceis delivered from the ingestible device) and the location where the jetimpacts the GI tissue of the subject.

“Jet stable length,” as used herein, refers to the distance from anopening (e.g., nozzle opening) of an ingestible device that adispensable substance delivered through the opening remains in the formof a jet.

“Jet velocity,” as used herein is the average fluid velocity across thecross-section of a jet at a given point in time.

As used herein, “peak jet velocity,” refers to the maximum jet velocityof a jet at the interface of the lumen and the surface of the GI tractfacing the lumen. In general, the peak jet velocity is achieved at thetime of initial delivery of the dispensable substance from theingestible device.

As used herein, “minimum jet velocity,” refers to the minimum velocityof a jet at the interface of the lumen and the surface of the GI tractfacing the lumen. In general, the minimum jet velocity is achieved atthe end of delivery of the dispensable substance from the ingestibledevice.

“Mean jet velocity” and “average jet velocity,” as used herein, refer tothe average velocity of a jet at the interface of the lumen and thesurface of the GI tract facing the lumen as determined over the timethat the ingestible device delivers the dispensable substance.

As used herein, “peak jet power” refers to the maximum power of a jet atthe interface of the lumen and the surface of the GI tract facing thelumen. In general, the peak jet power is achieved at the time of initialdelivery of the dispensable substance from the ingestible device.

As used herein, “minimum jet power,” refers to the minimum power of ajet at the interface of the lumen and the surface of the GI tract facingthe lumen. In general, the minimum jet power is achieved at the end ofdelivery of the dispensable substance from the ingestible device.

“Mean jet power” and “average jet power,” as used herein, refer to theaverage power of a jet at the interface of the lumen and the surface ofthe GI tract facing the lumen as determined over the time that theingestible device delivers the dispensable substance.

“Jet power during delivery,” as used herein, refers to the power of ajet at the interface of the lumen and the mucosa of the GI tract of asubject.

“Jet pressure,” as used herein, refers to the pressure of a jet at theinterface of the lumen and the surface of the GI tract facing the lumen.As an example, the jet pressure can be the pressure by the jet measuredat the intestinal wall. In some embodiments, jet pressure is referred toherein as “impact pressure.”

“Peak jet pressure,” as used herein, refers to the maximum pressure of ajet at the interface of the lumen and the surface of the GI tract facingthe lumen. In general, the peak jet pressure is achieved at the time ofinitial delivery of the dispensable substance from the ingestibledevice.

As used herein, “minimum jet pressure,” refers to the minimum pressureof a jet at the interface of the lumen and the surface of the GI tractfacing the lumen. In general, the minimum jet pressure is achieved atthe end of delivery of the dispensable substance from the ingestibledevice.

“Mean jet pressure” and “average jet pressure,” as used herein, refer tothe average pressure of a jet at the interface of the lumen and thesurface of the GI tract facing the lumen as determined over the timethat the ingestible device delivers the dispensable sub stance.

“Jet force,” as used herein, refers to the force of a jet at theinterface of the lumen and the surface of the GI tract facing the lumen.In some embodiments, jet force is referred to herein as “impact force.”

“Peak jet force,” as used herein, refers to the maximum force of a jetat the interface of the lumen and the surface of the GI tract facing thelumen. In general, the peak jet force is achieved at the time of initialdelivery of the dispensable substance from the ingestible device. Insome embodiments, peak jet force is referred to herein as “impactforce.”

As used herein, “minimum jet force,” refers to the minimum force of ajet at the interface of the lumen and the mucosa of the GI tract of asubject. In general, the minimum jet force is achieved at the end ofdelivery of the dispensable substance from the ingestible device.

“Mean jet force” and “average jet force,” as used herein, refer to theaverage pressure of a jet at the interface of the lumen and the surfaceof the GI tract facing the lumen as determined over the time that theingestible device delivers the dispensable sub stance.

As used herein, “fluid volume” refers to the volume of the dispensablesubstance contained in the ingestible device.

“Initial fluid volume,” as used herein, refers to the volume of thedispensable substance contained in the ingestible device just prior todelivery of the dispensable substance from the ingestible device.

“Final fluid volume,” as used herein, refers to the volume of thedispensable substance contained in the ingestible device just afterdelivery of the dispensable substance from the ingestible device hasended.

As herein, “delivered fluid volume” refers to the volume of dispensablesubstance delivered from the ingestible device. In some embodiments, thedelivered fluid volume is less than the fluid volume.

“End round” as used herein is the radius on the curve at the end of thehousing of the ingestible device.

“Fluid pressure” as used herein refers to the pressure in the fluidvolume.

As used herein, “peak fluid pressure” refers to maximum pressuregenerated in the fluid volume. Generally, the peak fluid pressure isachieved at initial delivery of the dispensable substance from theingestible device. In some embodiments, peak fluid pressure is referredto herein as “internal pressure on the pharmaceutical formulation in thedevice, prior to release from the device.”

As used herein, “minimum fluid pressure” refers to minimum pressuregenerated in the fluid volume. Generally, the minimum fluid pressure isachieved at the end of delivery of the dispensable substance from theingestible device.

“Fluid pressure during delivery,” as used herein, refers to the pressurein the fluid volume as it decreases during the delivery process.

As used herein, “nozzle” refers to a channel between a fluid reservoirspace and an external environment. Generally, in embodiments in which anozzle is used, pressure in the fluid volume generates a high speed flowof fluid through the nozzle to produce a fluid jet at the opening of thenozzle through which the dispensable substance leaves the ingestibledevice and enters an environment exterior to the ingestible device.

“Nozzle diameter,” as used herein, refers to the diameter of the openingof the nozzle at the opening of the nozzle through which the dispensablesubstance leaves the ingestible device and enters an environmentexterior to the ingestible device.

As used herein, “nozzle length” refers to the length of the opening ofthe nozzle.

“Nozzle stand-off distance,” as used herein, refers to the distancebetween: 1) the opening of the nozzle through which the dispensablesubstance leaves the ingestible device and enters an environmentexterior to the ingestible device; and 2) the interface of the lumen andthe surface of the GI tract facing the lumen.

As used herein, the “internal pressure” of an ingestible device refersto the pressure applied to a dispensable substance, such as atherapeutic agent, or a formulation containing a therapeutic agent,contained in the ingestible device prior to delivery of the dispensablesubstance from the ingestible device. In some embodiments, the internalpressure is provided by the drive force generator of the ingestibledevice. In certain embodiments, the internal pressure is greater thanthe fluid pressure. This may be due, for example, to friction, such asO-ring friction, acting on the drive coupling of the ingestible device.This friction is referred to herein as the “piston friction.”

“Nozzle pressure” as used herein refers to the pressure of a dispensablesubstance at a nozzle opening as measured at the surface facing theinterior of the nozzle as the dispensable substance is delivered fromthe ingestible device. In general, for a given ingestible device at agiven point in time, the nozzle pressure is approximately the same asthe fluid pressure.

“Topical delivery” or “topical administration,” as used herein, refersto a route of administration of a dispensable substance (for example, atherapeutic agent or a pharmaceutical formulation containing atherapeutic agent) where the dispensable substance is delivered to alocalized area of the body or to the surface of a body part, regardlessof the location of the effect; more particularly, the topicaladministration of the dispensable substance comprises releasing thedispensable substance to the lumen of the GI tract, a surface of the GItract facing the lumen, a mucous membrane and/or a lining of thegastrointestinal tract of a subject, including, but not limited to, asurface, mucous membrane or lining containing one or more disease sites,such as gastrointestinal mucosal lesions. The effect of the topicaldelivery or topical administration of the dispensable substance may belocal to, or away from (e.g., distal to), the site of the topicaladministration.

“Epithelial delivery” or “epithelial administration,” as used herein,refers to a route of administration of a dispensable substance (forexample, a therapeutic agent or a pharmaceutical formulation containinga therapeutic agent) where the dispensable substance is directlydelivered into the mucus or onto the epithelium, but not past theepithelial layer, of the GI tract of a subject, such as the small orlarge intestine, from which the dispensable substance can act locally orperipherally. In some embodiments of epithelial delivery or epithelialadministration, the therapeutic agent can move deeper into the GI tissue(i.e., past the epithelial layer) away from the site of direct delivery,such as, for example, via diffusion or active transport.

“Trans-epithelial delivery” or “trans-epithelial administration,” asused herein, refers to a route of administration of a dispensablesubstance (for example, a therapeutic agent or a pharmaceuticalformulation containing a therapeutic agent) where the dispensablesubstance is directly delivered through the epithelial layer of themucosa of the GI tract to the submucosa of the GI tract of a subject;optionally, at least a portion of the dispensable substance is directlydelivered past the epithelial layer to a region of the mucosa beneaththe epithelial layer. In embodiments of trans-epithelial delivery inwhich a portion of the dispensable substance is directly delivered to aregion of the mucosa beneath the epithelial layer, at least some (e.g.,all) of the portion of the dispensable substance is directly deliveredto the lamina propria. Once the therapeutic agent or a pharmaceuticalformulation containing a therapeutic agent is directly delivered pastthe epithelial layer of the GI tract, it is available for systemicexposure of the therapeutic agent to the subject.

The term “response” refers to a measurable response, including completeresponse (CR) and partial response (PR).

“Complete response” or “CR” as used herein refers to the disappearanceof all signs of disease or remission in response to treatment. This doesnot necessarily mean the disease has been cured.

“Partial response” or “PR” as used herein refers to a decrease of atleast 50% in the severity of disease in response to treatment.

“Beneficial response” of a patient to treatment with a therapeuticagent, as used herein, and similar wording, refers to the clinical ortherapeutic benefit imparted to a patient at risk for or suffering froma disease or condition. Such benefit includes cellular or biologicalresponses, a complete response, a partial response, a stable disease(without progression or relapse), or a response with a later relapse ofthe patient from or as a result of the treatment with the agent.

A patient's response can be assessed using any endpoint indicating abenefit to the patient, including, without limitation, (1) inhibition,to some extent, of disease progression, including slowing down andcomplete arrest; (2) reduction in the number of disease episodes and/orsymptoms; (3) reduction in lesional size; (4) inhibition (i.e.,reduction, slowing down or complete stopping) of disease cellinfiltration into adjacent peripheral organs and/or tissues; (5)inhibition (i.e., reduction, slowing down or complete stopping) ofdisease spread; (6) decrease of auto-immune response, which may, butdoes not have to, result in the regression or ablation of the diseaselesion; (7) relief, to some extent, of one or more symptoms associatedwith the disorder; (8) increase in the length of disease-freepresentation following treatment; and/or (9) decreased mortality at agiven point of time following treatment.

General Introduction

FIG. 1A schematically describes the different regions of healthyintestinal tissue, presented in a cross section. The regions include thelumen of the GI tract, the mucus of the GI tissue, the mucosa of the GItissue and the submucosa of the GI tissue. The mucosa of the GI tissueincludes the epithelial layer and the lamina propria. The muscularismucosae separates the mucosa from the submucosa. The muscularis extremais below the submucosa. FIG. 1B schematically describes correspondingregions of diseased intestinal tissue, presented in a cross section.

An ingestible device described herein can deliver a therapeutic agentvia topical delivery (without being directly delivered to the mucus,mucosa or submucosa), epithelial delivery (directly delivered to themucus or epithelium without being directly delivered past the epitheliallayer to the mucosa or submucosa) or trans-epithelial delivery (directlydelivered to the submucosa and/or into a region of the mucosa beneaththe epithelial layer, such as the lamina propria.

In general, the form of delivery may depend on the design of theingestible device and parameters used with the device (e.g., internalpressure, fluid pressure, number of nozzles, design of nozzles). Holdingother parameters constant, at relatively low fluid pressures and/orinternal pressures, the therapeutic agent may be topically delivered,while higher fluid pressures and/or internal pressures may result inepithelial delivery, and still higher fluid pressures and/or internalpressure may result in trans-epithelial delivery. Duringtrans-epithelial delivery, a bolus of the therapeutic agent initiallycontained in the dispensable substance may form within the submucosaand/or into a region of the mucosa beneath the epithelial layer, such asthe lamina propria.

In some embodiments, the following holds. The ingestible device isdesigned to deliver a dispensable substance, for example, a therapeuticagent or a pharmaceutical formulation containing a therapeutic agentthrough the epithelial layer of the mucosa of the GI tract. In someembodiments, the dispensable substance is a solution formulation;optionally, a suspension. In some embodiments, the dispensable substanceenters the submucosa and/or into a region of the mucosa beneath theepithelial layer, such as the lamina propria, of the small intestine,where it can be absorbed systemically. After the patient swallows thedevice, it passes through the GI tract and eventually reaches the smallintestine. The device includes a restraining mechanism, an optionally atriggering mechanism (e.g., a degradable and/or erodible coating, suchas an enteric coating, that partially or completely degrades and/orerodes when the device reaches the desired location in the GI tract).The desired location can be the small intestine or the large intestine.When the device is configured for trans-epithelial GI tract delivery tothe submucosa submucosa and/or into a region of the mucosa beneath theepithelial layer, such as the lamina propria, the preferred location canbe the small intestine. With the restraining element is removed,relative movement between certain components (e.g., sliding of acomponent) occurs such that one or more openings in the ingestibledevice (e.g., in a compartment containing the dispensable substance,such as a reservoir, sometimes referred to herein as the “drugreservoir,” “storage reservoir” or “substance reservoir”) become alignedwith one or more additional openings (e.g., one or more nozzles) in theingestible device (e.g., in the housing). With the ingestible device nowin this open position, a force (e.g., generated by a force generatorand/or transferred by a drive coupling, such as a membrane or a piston)forces the dispensable substance from the drug reservoir out of thedevice via the one or more openings (e.g., the one or more nozzles). Thedispensable substance is delivered as a jet of fluid (e.g., liquid)through the epithelial layer of the mucosa and directly into thesubmucosa and/or into a region of the mucosa beneath the epitheliallayer, such as the lamina propria, of the GI tract in the form of singleor multiple boluses. After swallowing the device, the device travelsthrough the GI tract (mouth, esophagus, stomach, duodenum, jejunum,ileum, cecum and colon), ultimately exiting the GI tract via the anus.

Thus, in general, the ingestible devices disclosed herein providedelivery of therapeutic agent to the GI tract of a subject. In oneaspect, the disclosure relates to trans-epithelial delivery of adispensable substance (e.g., a therapeutic agent or a formulationcomprising a therapeutic agent) to the GI tract of a subject.Accordingly, the disclosure provides an ingestible device that candirectly deliver a dispensable substance (e.g., a therapeutic agent or aformulation comprising a therapeutic agent) to the submucosa and/or intoa region of the mucosa beneath the epithelial layer, such as the laminapropria, of the GI tract of a subject, which may result in systemicexposure of the therapeutic agent to the subject. In such embodiments,the ingestible device is configured to directly deliver the dispensablesubstance past the epithelial cell layer of the mucosa and into thesubmucosa and/or into a region of the mucosa beneath the epitheliallayer, such as the lamina propria, of the GI tract, where thetherapeutic agent so delivered is available for systemic uptake. In someembodiments, systemic exposure of the therapeutic agent is achieved bytrans-epithelial delivery of the dispensable substance into thesubmucosa and/or into a region of the mucosa beneath the epitheliallayer, such as the lamina propria, of the small intestine, for example,in the duodenum, the jejunum, and/or the ileum. In some furtherembodiments, the trans-epithelial delivery directly delivers thedispensable substance into the submucosa and/or into a region of themucosa beneath the epithelial layer, such as the lamina propria, of theGI tract such that the percent systemic uptake of the therapeutic agentvia the trans-epithelial delivery relative to intravenous orsubcutaneous administration is at least about 10% (e.g., at least about15%, at least about 20%, at least about 25% or more).

In some embodiments, the direct delivery of the therapeutic agent to thesubmucosa and/or into a region of the mucosa beneath the epitheliallayer, such as the lamina propria, via trans-epithelial delivery mayalso or alternatively provide therapeutic effects locally and/or awayfrom (e.g., distal to) the site of the direct delivery.

In some embodiments, the trans-epithelial delivery may directly delivera first portion of the dispensable substance to the submucosa of the GItract, and a second portion of the dispensable substance to the mucosa,all or a further portion of which may be directly delivered to thelamina propria. In some embodiments, the second portion of thedispensable substance delivered to the mucosa, such as the laminapropria, of the GI tract via the trans-epithelial delivery may providetherapeutic effects locally and/or away from (e.g., distal to) the siteof the direct delivery.

In another aspect, the disclosure relates to epithelial delivery of adispensable substance (e.g., a therapeutic agent or a formulationcomprising a therapeutic agent) to the GI tract of a subject.Accordingly, the disclosure provides an ingestible device configured todirectly deliver a dispensable substance (e.g., a therapeutic agent or aformulation comprising a therapeutic agent) into the mucus, but not pastthe epithelial layer of the mucosa, of the small or large intestine,from which it may provide therapeutic effects locally and/or away from(e.g., distal to) the site of the direct delivery. In some furtherembodiments, the ingestible device directly delivers the dispensablesubstance such that it contacts the surface of the epithelial cell layerof the mucosa facing the lumen, but as previously noted, the epithelialdelivery does not directly delivery the dispensable substance past theepithelial layer of the mucosa. In some embodiments, the device isconfigured so that the dispensable substance is delivered from thedevice with sufficient force to provide the epithelial delivery, theforce being lower than that required for trans-epithelial delivery tothe GI tract. In some further embodiments, the epithelial deliverydirectly delivers the dispensable substance into the mucus of the GItract such that the percent systemic uptake of the therapeutic agent viathe epithelial delivery relative to intravenous or subcutaneousadministration is greater than that for topical delivery, but less thanfor trans-epithelial delivery. In other embodiments, the epithelialdelivery directly delivers the dispensable substance into the mucus ofthe GI tract such that the percent systemic uptake of the therapeuticagent via the epithelial delivery relative to intravenous orsubcutaneous administration is about 0.5% to about 10% or more (e.g.,about 0.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, or more).

In some embodiments of epithelial delivery, the therapeutic agentdirectly delivered into the mucus of the GI tract via the epithelialdelivery may undergo active or passive transport or diffusion past theepithelial layer. Once past the epithelial layer, the therapeutic agentmay provide therapeutic effects locally and/or away from (e.g., distalto) the site of the direct delivery. In some embodiments, thetherapeutic agent binds to a therapeutic target present in the GIepithelial layer or elicits other pharmacodynamic effects locally oraway from the site of delivery via immune cells or tissue in the GItract (e.g., dendritic cells, lymphocytes, mucosa-associated lymphoidtissue).

In yet another aspect, this disclosure relates to topical delivery of adispensable substance (e.g., a therapeutic agent or a formulationcomprising a therapeutic agent) to the GI tract of a subject.Accordingly, the disclosure provides an ingestible device configured todeliver the dispensable substance (e.g., a therapeutic agent or aformulation comprising a therapeutic agent) into the lumen and/or ontothe mucus or other surface (e.g., a diseased surface) of the GI tractfacing the lumen of the small or large intestine, from which it mayprovide therapeutic effects locally and/or away from (e.g., distal to)the site of delivery. In some embodiments, the device is configured sothat the dispensable substance is delivered from the device withsufficient force so that the dispensable substance is deliveredtopically, the force being lower than that required for the epithelialor the trans-epithelial delivery to the GI tract. In some embodiments,the topical delivery to the GI tract results in reduced systemic uptakeof the therapeutic agent compared to trans-epithelial delivery to the GItract, intravenous or subcutaneous delivery.

In some further embodiments, topical delivery delivers the dispensablesubstance into the lumen and/or onto the mucus or the other surfacefacing the lumen of the GI tract such that the percent systemic uptakeof the therapeutic agent via the topical delivery relative tointravenous or subcutaneous administration is less than about 20%, lessthan about 10%, less than about 5%, less than about 4%, less than about3%, less than about 2% or less than about 1%. In some embodiments, thetopical delivery to the GI tract results in negligible or no systemicuptake of the therapeutic agent compared to trans-epithelial delivery tothe GI tract, intravenous or subcutaneous delivery.

In some embodiments, the topically delivered dispensable substance mayspread over the mucus or other surface facing the lumen of the GI tract,thereby coating the surface of the GI tract at or away from (e.g.,distal to) the site of delivery. In some embodiments, upon or after thedispensable substance has been topically delivered, the therapeuticagent may undergo transport (e.g., diffusion) from the surface of themucus into the mucus, and optionally, active or passive transport ordiffusion past the epithelial layer of the mucosa.

In some embodiments, the mucus and/or epithelial layer of the mucosa maybe disrupted or even absent, such as in a patient having a disease orcondition of the GI tract. In such embodiments, the topical delivery ofthe dispensable substance to the GI tract of the patient may providedirect delivery of the dispensable substance to the surface of the GItract facing the lumen, such as mucosal tissue exposed by saiddisruption and/or absence (e.g., both the mucus layer and/or epitheliallayer are completely or partially absent or compromised in portions ofthe GI tract due to a disease or condition). For example, in someembodiments, the topical delivery of the dispensable substance to the GItract of the patient may provide topical delivery to one or more lesionsof the GI tract. In some embodiments, the disease or condition is aninflammatory bowel disease. In some further embodiments, theinflammatory bowel disease is ulcerative colitis. In some otherembodiments, the inflammatory bowel disease is Crohn's disease.

Accordingly, provided herein are new systemic delivery devices andmethods that deliver therapeutic agents into the small intestinal mucosaand/or submucosa by jet injection. Current methods of administration formost large molecule therapeutic agents are subcutaneous (SC),intramuscular (IM), or bolus intravenous (IV) injection targeting thesystemic circulation. The devices and methods described herein providean alternative route of administration to current injectablemedications, which can lead to greater convenience and compliance sincethey minimize or avoid the logistical challenges, patient compliance andadherence challenges, pain, and discomfort associated with traditionalroutes of administration.

Also, by providing a higher concentration of therapeutic in GI tissue,the devices and methods described herein are particularly well-suitedfor treatment of diseases and conditions of the endoderm, including theliver.

In some embodiments of any of the devices or methods described herein,the pharmaceutical composition is an ingestible device, that includes: ahousing; a drug reservoir located within the housing and containing thetherapeutic; a pre-pressurized air reservoir; a sliding mechanism; andan exit nozzle configured to allow the therapeutic agent to be releasedout of the housing from the reservoir and into the submucosa and/or themucosa (e.g., into the lamina propria) of the gastrointestinal tract.

In some embodiments of the devices or methods described herein, thetherapeutic is released at a location in the large intestine of thesubject. In some embodiments of any of the devices or methods describedherein, the location is in the proximal portion of the large intestine.In some embodiments of any of the devices or methods described herein,the location is in the distal portion of the large intestine.

In some embodiments of any of the devices or methods described herein,the therapeutic is released at a location in the ascending colon of thesubject. In some embodiments of any of the devices or methods describedherein, the location is in the proximal portion of the ascending colon.In some embodiments of any of the devices or methods described herein,the location is in the distal portion of the ascending colon.

In some embodiments of any of the devices or methods described herein,the therapeutic is released at a location in the cecum of the subject.In some embodiments of any of the devices or methods described herein,the location is in the proximal portion of the cecum. In someembodiments of any of the devices or methods described herein, thelocation is in the distal portion of the cecum.

In some embodiments of any of the devices or methods described herein,the therapeutic is released at a location in the sigmoid colon of thesubject. In some embodiments of any of the devices or methods describedherein, the location is in the proximal portion of the sigmoid colon. Insome embodiments of any of the devices or methods described herein, thelocation is in the distal portion of the sigmoid colon.

In some embodiments of any of the devices or methods described herein,the therapeutic is released at a location in the transverse colon of thesubject. In some embodiments of any of the devices or methods describedherein, the location is in the proximal portion of the transverse colon.In some embodiments of any of the devices or methods described herein,the location is in the distal portion of the transverse colon.

In some embodiments of any of the devices or methods described herein,the therapeutic is released at a location in the descending colon of thesubject. In some embodiments of any of the devices or methods describedherein, the location is in the proximal portion of the descending colon.In some embodiments of any of the devices or methods described herein,the location is in the distal portion of the descending colon.

In some embodiments of any of the devices or methods described herein,the therapeutic is released at a location in the small intestine of thesubject. In some embodiments of any of the devices or methods describedherein, the location is in the proximal portion of the small intestine.In some embodiments of any of the devices or methods described herein,the location is in the distal portion of the small intestine.

In some embodiments of any of the devices or methods described herein,the therapeutic is released at a location in the duodenum of thesubject. In some embodiments of any of the devices or methods describedherein, the location is in the proximal portion of the duodenum. In someembodiments of any of the devices or methods described herein, thelocation is in the distal portion of the duodenum.

In some embodiments of any of the devices or methods described herein,the therapeutic is released at a location in the jejunum of the subject.In some embodiments of any of the devices or methods described herein,the location is in the proximal portion of the jejunum. In someembodiments of any of the devices or methods described herein, thelocation is in the distal portion of the jejunum.

In some embodiments of any of the devices or methods described herein,the therapeutic is released at a location in the ileum of the subject.In some embodiments of any of the devices or methods described herein,the location is in the proximal portion of the ileum. In someembodiments of any of the devices or methods described herein, thelocation is in the distal portion of the ileum.

Device Description General

In general, the ingestible device is suitable for swallowing by apatient and for safely and effectively passing through the GI tract ofthe patient. Generally, the device can be in the shape of a capsule, apill or any other swallowable form that may be orally consumed by thesubject. In some embodiments, the ingestible device can be swallowedvoluntarily under medical supervision or in a home use environment withinstruction provided ahead of subsequent ingestion. Generally,ingestible devices are intended for single subject, single use. Theingestible device can have a density high enough to cause the ingestibledevice to sink within human stomach fluid, e.g., the unfilled ingestibledevice can have a density of greater than 1.01 g/cm³. The ingestibledevice can have maximum dimensions that allow the ingestible device topass through an average human GI tract. In some embodiments, theingestible device is configured to prevent tumbling in the smallintestine of a human. For example, the ingestible device is ofsufficient length whereby it will not tumble in the small intestine of ahuman before, during, or after the dispensable substance is released.Generally, the ingestible device is configured to deliver a sufficientamount of therapeutic agent contained in the dispensable substance to beeffective for its intended purpose. In general, the ingestible device'spatient-contacting portions (e.g., exterior surface) and dispensablesubstance-contacting portions are biocompatible. Preferably, the devicecan withstand an indirect bite force without damaging the housing damageor resulting in leakage. As an example, when containing the dispensablesubstance, the ingestible device can withstand a bite force of at leastabout 60 Newtons (N). Generally, unless otherwise intended (seediscussion below) components of the ingestible device can withstandexposure to a pH range expected in the human GI tract withoutsubstantial loss of functionality, substantial structural damage, orsubstantial leakage. As an example, in some embodiments, the ingestibledevice can withstand submersion in a pH 1.5±0.5 fluid environment for atleast about 24 hours without substantial loss of functionality,substantial structural damage, or substantial leakage. In general, theingestible device can maintain an external fluid barrier between theinside of the ingestible device and the GI tract of the subject duringtransit therethrough. Generally, the ingestible device can withstandexternal fluid pressures to which it is exposed during use withoutsubstantial loss of functionality, substantial structural damage, orsubstantial leakage. As an example, in some embodiments, the ingestibledevice undergoes no substantial loss of functionality, substantialstructural damage, or substantial leakage when exposed to a sustainedpressure of at least about 2 psig for at least about 24 hours and/orwhen exposed to a momentary pressure of at least about 5 psig momentarypressure for at least about 1 minute.

In general, an ingestible device disclosed herein includes the followingfeatures.

Housing

In some embodiments, the ingestible device comprises a housingconfigured to maintain its mechanical integrity during use of theingestible device. In some embodiments, the housing has a first portionand a second portion. In some further embodiments, the housing has afirst actuation component on the housing, and a second actuationcomponent within the housing. In some embodiments, a storage reservoiris located within the housing, wherein the storage reservoir isconfigured to store a dispensable substance. In some embodiments, thehousing has an opening in fluid communication with the storagereservoir. In some embodiments, the ingestible device employs anelectrolytic mechanism for creating one or more openings in theingestible device, wherein a substance can be dispensed through saidopening as described in PCT Application Number PCT/US2019/021814, whichpublished as WO2019178071, and which is incorporated by referenceherein. For example, the housing may comprise an external electrolyticcircuit (electrolytically erodible surface being on the exterior of thedevice), whereby the surrounding gastric fluids are the electrolyte thatcompletes an electrolytic circuit between anode and cathode. Withsufficient bias voltage (e.g., 1.5-15 volts, such as 3-5 volts), theanode will dissolve or erode electrolytically and thus create an openingin the housing within a desired time interval. In some embodiments, theone or more openings created by an electrolytic mechanism are coupled toone or more nozzles, thereby allowing for trans-epithelial, epithelial,or topical delivery as described herein. In some embodiments aningestible device includes an enteric coating on the housing. In certainembodiments, the enteric coating covers only certain regions of thehousing. The housing may be designed to withstand the chemical andmechanical environment of the GI tract (e.g., effects of musclecontractile forces and concentrated hydrochloric acid in the stomach). Abroad range of materials that may be used for the housing. Examples ofthese materials include, but are not limited to, thermoplastics,fluoropolymers, elastomers, stainless steel, and glass complying withISO 10993 and USP Class VI specifications for biocompatibility; and anyother suitable materials and combinations thereof. In certainembodiments, these materials may further include liquid silicone rubbermaterial with a hardness level of 10 to 90 as determined using adurometer (e.g., MED-4942™ manufactured by NuSil™), a soft biocompatiblepolymer material such as, but not limited to, polyvinyl chloride (PVC),polyethersulfone (PES), polyethylene (PE), polyurethane (PU) orpolytetrafluoroethylene (PTFE), and a rigid polymer material coated witha biocompatible material that is soft or pliable (e.g., a poly(methylmethacrylate) (PMMA) material coated with silicone polymer). Use ofdifferent materials for different components may enablefunctionalization of certain surfaces for interaction with proteins,antibodies, and other biomarkers. For example, Teflon® may be used as amaterial in the ingestible device for movable components in order toreduce friction between these components. Other example materials mayinclude other materials commonly used in micro-fabrication, such aspolydimethylsiloxane (PDMS), borosilicate glass, and/or silicon.Although specific materials may be referred to herein as being used toconstruct the device for illustrative purposes, the materials recitedare not intended to be limiting, and one skilled in the art may easilyadapt the device to use any number of different materials withoutaffecting the overall operation or functionality of the device. In someembodiments, the housing of the ingestible device may be manufacturedfrom a type of plastic, such as a photosensitive acrylic polymermaterial or an inert polycarbonate material. The housing may also beformed using material that can be sterilized by chemicals. In someembodiments, the wall of the housing may have a thickness of, forexample, from about 0.5 millimeter to about 1 millimeter. In someembodiments, in addition to being biocompatible, the material from whichthe housing is made is non-ferric and non-magnetic. Such materialsinclude various plastics (e.g., PVC, or polycarbonate). Optionally, thehousing can include a metal-based material, such as an alloy, stainlesssteel or a substantially pure metal. Such materials can be sterilizedwithout affecting the mechanical workings of the ingestible device orthe exterior surface of the ingestible device. In some embodiments, themetal-based material is compatible with the dispensable substance overlong duration of storage. A wide variety of stainless steel alloyssatisfy these criteria, including SAE grades 303, 304, 304L, 316, 316L,440. In consideration of nickel content, purity, and/or traceability, insome embodiments, the stainless steel grade is approved for use as asurgical implant material, such as ASTM grades F138, F1314, F1586,F2229, or F2581. The walls of the housing of the ingestible devicegenerally are sufficiently thick to withstand internal and externalpressures to which they are exposed without substantial loss offunctionality, substantial structural damage, or substantial leakage. Ingeneral, the walls of the housing are desirably as thin as possible toenhance the volume available for containing dispensable substance. As anexample, in some embodiments, the walls are from about 0.05 mm to about0.5 mm thick (e.g., if made of metal-based material, such as stainlesssteel) or from about 0.1 to about 1 mm thick (e.g., if made of plastic,such as polycarbonate). In general, the housing is made of material witha thermal expansion coefficient low enough that the device does notsubstantially deform at temperatures encountered during shipping andstorage, or within the GI tract. In some embodiments, the walls of thehousing are made of an electrolytically erodible surface as described inPCT/US2019/021814, which published as WO2019178071. For example, in someembodiments, the housing includes an electrolytically erodible valvecoupled to a nozzle for exposing the liquid volume to its surroundingenvironment. The exposed metal anode material acting as valve caninclude a metal alloy or substantially pure metal that is acceptable forhuman ingestion from consideration of its biocompatibility in theamounts electrolyzed during opening of the valve. It can be desirable tohave the thickness of metal in the valve area be small (e.g., to reducethe time and amount of current used to open the valve). For example, themetal portion of the drug container can be 0.025 mm thick across adiameter that matches or slightly exceeds the diameter of the couplednozzle (e.g., 0.60 mm). In general, the thickness of the metal in thevalve area can be in the range 0.002 mm to 0.200 mm.

In some embodiments, the housing of an ingestible device is assembledfrom multiple modules. For example, in some embodiments, the housing isassembled from two modules. In such embodiments, one of the modules cancontain the dispensable substance (“drug module”), and the other modulecan contain the drive force generator and the drive coupling (“drivemodule”). Typically, the drug module includes a housing part ofappropriate size, shape and material(s) as discussed herein. Usually,the housing part is sterilized, and dispensable substance issubsequently disposed within the housing under aseptic conditions.Optionally a sterile seal (e.g., a sterile foil seal) is incorporatedinto the drug module. The components of the drug module (e.g., a housingpart, a drive force generator, a drive coupling) are assembled in aclean environment. The drug module and the drive module are subsequentlycombined to form the ingestible device. Representative examples ofmodules, their separate assembly, and their combination to form aningestible device, are provide elsewhere herein.

Generally, an ingestible device is sized and shaped for relatively safeand effective movement and intended use within the GI tract of thesubject. In certain embodiments, an ingestible device is a capsulehaving an industry standard size. For example, in some embodiments, aningestible device is configured as a 00 capsule or a 000 capsule.

In certain embodiments, the housing of an ingestible device has a lengthof at least about 20 mm (e.g., at least about 21 mm, at least about 22mm, at least about 23 mm) and/or at most about 28 mm (e.g., at mostabout 27 mm, at most about 26 mm).

In some embodiments, the housing of an ingestible device has a diameterof at least about 7 mm (e.g., at least about 7.5 mm, at least about 8mm, at least about 8.5 mm, at least about 9 mm, at least about 9.5 mm)and/or at most about 12 mm (e.g., at most about 11.5 mm, at most about11 mm, at most about 10.5 mm, at most about 10 mm, at most about 9.5 mm,at most about 9 mm).

In certain embodiments, the housing of an ingestible device has anaspect ratio (ratio of length to width) of at least about 0.75 (e.g. atleast about 1) and/or at most about 4 (e.g., at most about 3, at mostabout 2). In some embodiments, the housing of an ingestible device hasan aspect ratio of from about 0.75 to 4 (e.g., from about 1 to about 3,from about 1 to about 2). For example, in some embodiments, the housingaspect ratio is about 1.5:1 (length:diameter). In some otherembodiments, the housing aspect ratio is about 2:1 (length:diameter).

In certain embodiments, the housing of an ingestible device has a wallthickness of at least about 0.05 mm (e.g., at least about 0.5 mm, atleast about 0.6 mm, at least about 0.7 mm) and/or at most about 1 mm(e.g., at most about 0.9 mm, at most about 0.8 mm). In certainembodiments, an ingestible device has a wall thickness of from about0.05 mm to about 0.5 mm. In some embodiments, an ingestible device has awall thickness of from about 0.1 mm to about 1 mm. In certainembodiments, one region of the housing of an ingestible device may havea wall thickness that is different from that of a different region ofthe housing of the ingestible device.

In some embodiments, the housing of an ingestible device has an endround that is spline-shaped or that is spherical. In certainembodiments, an ingestible device has an end round that is from about 1mm to about 2 mm (e.g., about 1.5 mm). In some embodiments, aningestible device has an end round that is from about 4 mm to about 4.5mm (e.g., about 4.25 mm). In certain embodiments, an ingestible devicehas an end round that is from about 4.9 to about 5 mm (e.g., about 4.95mm). In some embodiments, an ingestible device has an end round that isfrom about 5.4 mm to about 5.6 mm (e.g., about 5.5 mm).

In certain embodiments, the housing of an ingestible device has aninternal volume of at least about 700 μL (e.g., at least about 750 μL,at least about 800 μL, at least about 850 μL) and/or most about 1700 μL(e.g., at most about 1650 μL, at most about 1600 μL, at most about 1500μL, at most about 1400 μL, at most about 1300 μL, at most about 1200μL).

In an exemplary embodiment, the housing of an ingestible device has adiameter of about 11 mm, a length of about 26 mm, a wall thickness ofabout 0.8 mm, an end round of about 1.5 mm, and an internal volume ofabout 1685 μL.

In another exemplary embodiment, the housing of an ingestible device hasa diameter of about 11 mm, a length of about 26 mm, a wall thickness ofabout 0.8 mm, an end round of about 5.5 mm (spherical), and an internalvolume of about 1475 μL.

In a further exemplary embodiment, the housing of an ingestible devicehas a diameter of about 9.9 mm, a length of about 26 mm, a wallthickness of about 0.8 mm, an end round of about 1.5 mm, and an internalvolume of about 1315 μL.

In yet another exemplary embodiment, the housing of an ingestible devicehas a diameter of about 9.9 mm, a length of about 26 mm, a wallthickness of about 0.8 mm, an end round of about 4.95 mm (spherical),and an internal volume of about 1177 μL.

In a further exemplary embodiment, the housing of an ingestible devicehas a diameter of about 8.5 mm, a length of about 23.3 mm, a wallthickness of about 0.7 mm, an end round of about 1.5 mm, and an internalvolume of about 861 μL.

In still a further exemplary embodiment, the housing of an ingestibledevice has a diameter of about 8.5 mm, a length of about 23.3 mm, a wallthickness of about 0.7 mm, an end round of about 4.25 mm (spherical),and an internal volume of about 773 μL.

In yet a further exemplary embodiment, the housing of an ingestibledevice has a diameter of about 8.5 mm, a length of about 23.3 mm, a wallthickness of about 0.7 mm, an end round that is spline-shaped, and aninternal volume of about 820 μL.

Fluid Volume

The ingestible device includes a fluid volume to contain a dispensablesubstance (e.g., a liquid, a suspension). In some embodiments, the fluidvolume is completely disposed within the housing. Optionally, the fluidvolume can be defined by a storage reservoir. Such a storage reservoircan be a component that can be prepared separately from the housing. Insuch a storage reservoir, the dispensable substance can be disposed inthe storage reservoir before the storage reservoir is associated withthe ingestible device.

Dispensable Substance

The device may include one or more dispensable substances, with eachdispensable substance including one or more therapeutic agents and/orone or more pharmaceutical formulations including one or moretherapeutic agents.

Nozzles

In some embodiments, an ingestible device includes one or more nozzlesin fluid communication with the one or more openings in the ingestibledevice. The nozzle(s) is(are) configured so that the dispensablesubstance through the nozzle(s) when the dispensable substance isdelivered from the ingestible device. In general, a nozzle can have anydesired size and shape appropriate for the desired type of delivery of adispensable substance from the ingestible device. In certainembodiments, a nozzle has a shape and/or size appropriate fortrans-epithelial delivery, epithelial delivery or topical delivery. Insome embodiments, an ingestible device includes more than one nozzle.For example, an ingestible device can include, for example, up to 50nozzles (e.g., up to 40 nozzles, up to 35 nozzles, up to 30 nozzles, upto 25 nozzles, up to 20 nozzles, up to 15 nozzles, 10 nozzles). In someembodiments, an ingestible device includes from 2 nozzles to 50 nozzles.In certain embodiments, an ingestible device includes 2 nozzles, threenozzles, four nozzles, five nozzles, six nozzles, seven nozzles, eightnozzles, 10 nozzles, 20 nozzles, 30 nozzles, 36 nozzles, 40 nozzles, 50nozzles). In some embodiments, the nozzles are arranged at evenintervals (optionally pair-wise if an even number of nozzles are used)around the circumference of the device.

Restraining Mechanism

In some embodiments, the ingestible device comprises a restrainingmechanism. Generally, a restraining mechanism has a first state in whichit is configured to prevent the dispensable substance from exiting theingestible device via the opening(s), and a second state in which it isconfigured so that it does not prevent the dispensable substance fromexiting the ingestible device via the opening(s). The restrainingmechanism can be configured to transition from its first state to itssecond state when it is exposed to a triggering condition. Therestraining mechanism may be provided by one or more restrainingelements. The restraining elements can have a first state in which theyare configured to prevent the dispensable substance from exiting theingestible device via the openings, and a second state in which they areconfigured to allow the dispensable substance to exit the ingestibledevice via the openings. The restraining elements can be configured totransition from the first state to the second state when the restrainingelements are exposed to a triggering condition. In some embodiments, therestraining elements comprise a first type of restraining element and asecond type of restraining element different from the first type ofrestraining element. The first type of restraining element can beconfigured to transition to its second state before the second type ofrestraining element transitions to its second state. In someembodiments, a restraining elements comprises a lid, a pin, a band, aplug, a dowel, a clasp, a clamp, a flange, a rivet, or any combinationthereof. In some embodiments, the restraining elements comprise aplasticizer such as triethyl citrate (TEC). In some embodiments, therestraining elements comprise a degradable and/or erodible material,such as, for example, an enteric material. The enteric material may bedegradable and/or erodible in the small intestine of the GI tract, ormay be degradable and/or erodible in the large intestine of the GItract, for example, the colon. In some embodiments, a restrainingmechanism can be a mechanism that prevents the dispensable substancefrom being delivered from the ingestible device even when the driveforce generator (or optionally the drive coupling) applies an internalforce. For example, such a restraining can be an element (e.g., a pin, aband, a plug) in the opening (e.g., nozzle opening) through which thedispensable substance can be delivered from the ingestible device. Sucha restraining element can be formed, for example, of a material thatdegrades and/or erodes as discussed above.

Triggering Mechanism

In some embodiments, the ingestible device comprises a triggeringmechanism. In some embodiments, a triggering mechanism is configured tocause the dispensable substance within the fluid volume to be releasedunder one or more triggering conditions. In some embodiments, atriggering mechanism initiates a drive force generator. In someembodiments, a triggering mechanism incorporates a mechanical featurelike a restraining mechanism. As an example, one or more restrainingelements degrade and/or erode in the presence of certain GI tractconditions (e.g., pH greater than 5), thereby triggering a drive forcegenerator, such as a compressed spring. As another example, a spring mayhave a piercing element that pierces a cylinder with compressed gas,whereby the released gas acts as a force applied to a dispensablesubstance. In certain embodiments, a triggering mechanism incorporatesan electrical feature. For example, an enteric coating degrades and/orerodes in the presence of certain GI tract conditions (e.g., pH greaterthan 5), thereby exposing conductors to intestinal fluid, which acts asa liquid conductor to triggering the drive force generator. In someembodiments, a triggering condition relates to a condition of the GItract. In some embodiments, the condition of the GI tract comprises atleast one condition selected from the group consisting of temperature,pH, presence of one or more enzymes, and time. In some more particularembodiments, the condition of the GI tract is a pH of greater than 5. Incertain embodiments, the triggering mechanism is configured so that therelease mechanism is autonomously triggered (e.g., due to degradation,dissolution and/or erosion of the restraining mechanism due toconditions in the GI tract).

In some embodiments of any of the devices or methods described herein,the releasing of the therapeutic is triggered by one or more of: a pH inthe jejunum of about 6.1 to about 7.2, a pH in the mid small bowel ofabout 7.0 to about 7.8, a pH in the ileum of about 7.0 to about 8.0, apH in the right colon of about 5.7 to about 7.0, a pH in the mid colonof about 5.7 to about 7.4, or a pH in the left colon of about 6.3 toabout 7.7, such as about 7.0.

Drive Force Generator

The drive force generator is configured to provide the requisite forceto the dispensable substance such that, when the restraining mechanismis removed, the dispensable substance is delivered from the ingestibledevice as desired. The drive force generator can apply force usingdifferent mechanisms, including, for example, a compressed gas, a gasgenerated by chemical reaction, a spring, a liquid-gas mixture, animpact ram, a sudden expansion caused by a controlled exothermicreaction, or the like. When the drive force generator is a spring, thespring can have one or more of the following properties: the outerdiameter of the spring is smaller than the inner diameter of theingestible device; the compressed length of the spring is minimized toleave more space for dispensable substance; the spring is of a conicalshape, potentially with a reduction in the solid length of the spring;the free length of the spring is maximized and larger than the freelength of the inner cavity of the ingestible device to ensure anacceptable driving pressure is provided throughout the entire time stepof delivery; and the spring rate is large enough to provide acceptablepressure from the beginning until the end of delivery of the dispensablesubstance. Examples of springs include parallel springs, wave springsand conical springs. Examples of chemical reactants include an airbaginflator, a hydrogen cell (e.g., a Varta hydrogen cell), sodiumbicarbonate and acid (e.g., alka seltzer and water on board theingestible device, alka seltzer and GI tract fluid). Examples ofcompressed gas include a gas charged within the ingestible device, and acontainer (e.g., cylinder) of compressed gas. In some embodiments, thecompressed gas is a gas cylinder from Picocyl. Exemplary gas cylindersare disclosed, for example, in US 2017-0258583, which is incorporated byreference herein. An example of a liquid-gas mixture is liquidnitrogen/HFA (hexafluoroacetone)/propane. An example of an impact ram isa two-phase spring/ram. Other examples of drive force generators includea wax actuator, heat generated by electric power (Peltier effect-basedmechanism), and a mechanical puncture of tissue followed by delivery.

Drive Coupling

In general, the drive force coupling transfers a force from the driveforce generator to the dispensable substance. Examples of a drivecoupling include a piston and a membrane. Examples of membranes includeballoons and elastomeric materials. An example of a piston is an O-ringsealed piston. In some embodiments, a piston is provided by a gascylinder, e.g., with added O-rings or a custom housing. In someembodiments, a drive coupling is a vein, such as a rotating vein. Incertain embodiments, a drive coupling is a double piston configured tocounteract cap impact. In certain embodiments, a drive coupling is acollapsing bag, such as a collapsing foil bag. In some embodiments, adrive coupling is a collapsing bellows.

Storage Reservoir

In some embodiments, an ingestible device includes a storage reservoirconfigured to store a dispensable substance. In some embodiments, thestorage reservoir stores the dispensible substance. In some embodiments,the storage reservoir is completely disposed within the housing.

FIG. 2 is a schematic representation of an ingestible device 200 whichincludes a housing 202, a fluid volume 204 containing a dispensablesubstance, a nozzle 206 with a nozzle opening 208, a restrainingmechanism 210, a triggering mechanism 212, a drive force generator 214and drive coupling 216. During use, ingestible device 200 is swallowedby a subject and traverses the GI tract. At an appropriate location, thetriggering mechanism 212 is triggered, allowing the drive forcegenerator to apply pressure to the drive coupling 216, which thenapplies pressure to the fluid volume such that at least some of thedispensable substance is delivered out of fluid volume 204, through thenozzle 206, and out of the device 200 via the nozzle opening 208. Insome embodiments, the internal pressure is applied, even before thetriggering mechanism 212 is triggered. As an example, at an appropriatelocation, the triggering mechanism 212 is triggered, allowing the drivecoupling 216 to apply pressure to the fluid volume 204. In certainembodiments, the internal pressure is not applied until the triggeringmechanism 212 is triggered.

Device for Trans-Epithelial Delivery

Generally, trans-epithelial delivery can be achieved at any desiredlocation within the GI tract of a subject. In some embodiments,trans-epithelial delivery is achieved in the small intestine of thesubject, such as, for example, in the duodenum, the jejunum and/or theileum. In certain embodiments, trans-epithelial delivery is achieved inthe large intestine of the subject, such as, for example, the cecum orthe colon.

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having a peakjet power of from at least about 1 Watt (e.g., at least about 1.1 Watts,at least about 1.2 Watts, at least about 1.3 Watts, at least about 1.4Watts, at least about 1.5 Watts, at least about 1.6 Watts, at leastabout 1.7 Watts, at least about 1.8 Watts) and/or at most about 3 Watts(e.g., at most about 2.9 Watts, at most about 2.8 Watts, at most about2.7 Watts, at most about 2.6 Watts, at most about 2.5 Watts, at mostabout 2.4 Watts, at most about 2.3 Watts, at most about 2.2 Watts, atmost about 2.1 Watts). In some embodiments, an ingestible device fortrans-epithelial delivery is configured to deliver a jet of thedispensable substance having a peak jet power of from about 1 Watt toabout 3 Watts (e.g., of from about 1.3 Watts to about 2.8 Watts, of fromabout 1.5 Watts to about 2.5 Watts).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having aminimum jet power of at least about 0.1 W (e.g., at least about 0.2 W,at least about 0.3 W) and/or at most about 0.6 W (e.g., at most about0.5 W, at most about 0.4 W). In some embodiments, a device fortrans-epithelial delivery is configured to deliver a jet of thedispensable substance having a minimum jet power of from about 0.1 W toabout 0.6 W (e.g., from about 0.2 W to about 0.5 W, from about 0.3 W toabout 0.4 W).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having anaverage jet power of at least about 0.5 W (e.g., about 0.8 W, about 1 W)and/or at most about 2 W (e.g., at most about 1.7 W, at most about 1.5W). In some embodiments, a device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having anaverage jet power of from about 0.5 W to about 2 W (e.g., from about 0.8W to about 1.7 W, from about 1 W to about 1.5 W). Generally, aningestible device for trans-epithelial delivery is configured to delivera jet of the dispensable substance having a peak jet pressure of atleast about 100 psig (e.g., at least about 110 psig, at least about 120psig, at least about 130 psig, at least about 140 psig, at least about150 psig, at least about 160 psig, at least about 170 psig, at leastabout 180 psig, at least about 190 psig) and/or at most about 250 psig(e.g., at most about 240 psig, at most about 230 psig, at most about 220psig, at most about 210 psig). In certain embodiments, an ingestibledevice for trans-epithelial delivery is configured to deliver a jet ofthe dispensable substance having a peak jet pressure of from about 100psig to about 250 psig (e.g., from about 140 psig to about 225 psig,from about 180 psig to about 205 psig).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having aminimum jet pressure of at least about 30 psig (e.g., at least about 40psig, at least about 50 psig) and/or at most about 80 psig (e.g., atmost about 70 psig, at most about 60 psig. In some embodiments, aningestible device for trans-epithelial delivery is configured to delivera jet of the dispensable substance having a minimum jet pressure of fromabout 30 psig to about 80 psig (e.g., from about 40 psig to about 70psig, from about 50 psig to about 60 psig).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having anaverage jet pressure of 60 psig (e.g., at least about 80 psig, at leastabout 100 psig) and/or at most about 160 psig (e.g., at most about 140psig, at most about 120 psig). In some embodiments, an ingestible devicefor trans-epithelial delivery is configured to deliver a jet of thedispensable substance having an average jet pressure of from about 60psig to about 160 psig (e.g., from about 80 psig to about 140 psig, fromabout 100 psig to about 120 psig).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having a peakjet force of at least about 0.09 Newton (N) (e.g., at least about 0.1 N,at least about 0.11 N, at least about 0.12 N, at least about 0.13N)and/or at most about 0.15 N (e.g., at most about 0.14 N). In someembodiments, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having a peakjet force of from about 0.09 N to about 0.15 N (e.g., from about 0.1 Nto about 0.14 N, from about 0.11 N to about 0.14 N).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having aminimum jet force of at least about 0.01 N (e.g., at least about 0.02 N,at least about 0.03 N) and/or at most about 0.06 N (e.g., at most about0.05 N at most about 0.04 N). In some embodiments, an ingestible devicefor trans-epithelial delivery is configured to deliver a jet of thedispensable substance having a minimum jet force of from about 0.01 N toabout 0.06 N (e.g., from about 0.02 N to about 0.05 N, from about 0.03 Nto about 0.04 N).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having anaverage jet force of at least about 0.05 N (e.g., at least about 0.06 N,at least about 0.07 N) and/or at most about 0.1 N (e.g., at most about0.09 N, at most about 0.08 N). In some embodiments, an ingestible devicefor trans-epithelial delivery is configured to deliver a jet of thedispensable substance having an average jet force of from about 0.05 Nto about 0.1 N (e.g., from about 0.06 N to about 0.09 N, from about 0.07N to about 0.08 N).

Generally, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having a peakjet velocity of at least about 25 meters per second (m/s) (e.g., atleast about 26 m/s, at least about 27 m/s, at least about 28 m/s, atleast about 29 m/s, at least about 30 m/s, at least about 31 m/s, atleast about 32 m/s, at least about 34 m/s, at least about 35 m/s, atleast about 36 m/s) and/or at most about 45 m/s (e.g., at most about 44m/s, at most about 43 m/s, at most about 42 m/s, at most about 41 m/s,at most about 40 m/s, at most about 39 m/s, at most about 38 m/s, atmost about 37 m/s). In some embodiments, an ingestible device fortrans-epithelial delivery is configured to deliver a jet of thedispensable substance having a peak jet velocity of from about 25 m/s toabout 45 m/s (e.g., from about 30 m/s to about 42 m/s, from about 34 m/sto about 39 m/s, about 36.5 m/s).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having aminimum jet velocity of at least about 15 m/s (e.g., at least about 16m/s, at least about 17 m/s) and/or at most about 22 m/s (e.g., at mostabout 21 m/s, at most about 20 m/s). In some embodiments, an ingestibledevice for trans-epithelial delivery is configured to deliver a jet ofthe dispensable substance having a minimum jet velocity of from about 15m/s to about 22 m/s (e.g., from about 16 m/s to about 21 m/s, from about17 m/s to about 20 m/s).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of the dispensable substance having anaverage jet velocity of at least about 20 m/s (e.g., at least about 25m/s) and/or at most about 35 m/s (e.g., at most about 30 m/s). In someembodiments, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of dispensable substance having an averagejet velocity of from about 20 m/s to about 30 m/s (e.g., about 20 m/s,about 21 m/s, about 22 m/s, about 23 m/s, about 24 m/s, about 25 m/s,about 26 m/s, about 27 m/s, about 28 m/s about 29 m/s, about 30 m/s). Incertain embodiments, an ingestible device for trans-epithelial deliveryis configured to deliver a jet of dispensable substance having anaverage jet velocity of from about 25 m/s to about 35 m/s (e.g., about25 m/s, about 26 m/s, about 27 m/s, about 28 m/s, about 29 m/s, about 30m/s, about 31 m/s, about 32 m/s, about 33 m/s about 34 m/s, about 35m/s).

In general, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of a dispensable substance having a jetstable length of at least about 0.5 millimeter (mm) (e.g., at leastabout 1 mm, at least about 1.5 mm, at least about 2 mm, at least about2.5 mm, at least about 3 mm, at least about 3.5 mm, at least about 4 mm,at least about 4.5 mm, at least about 5 mm) and/or at most about 20 mm(e.g., at most about 15 mm, at most about 10 mm). In certainembodiments, an ingestible device for trans-epithelial delivery isconfigured to deliver a jet of a dispensable substance having a jetstable length of from about 0.5 mm to about 20 mm (e.g., from about 2 mmto about 20 mm, from about 5 mm to about 20 mm).

In some embodiments, an ingestible device for trans-epithelial deliveryis configured to deliver a jet of a dispensable substance having a jetdiameter of at least about 0.1 mm (e.g., at least about 0.2 mm, at leastabout 0.3 mm, at least about 0.4 mm) and/or at most about 2 mm (e.g., atmost about 1.5 mm, at most about 1 mm, at most about 0.9 mm, at mostabout 0.8 mm, at most 0.7 mm, at most about 0.6 mm, at most about 0.5mm). For example, such an ingestible device for trans-epithelialdelivery is configured to deliver a jet of a dispensable substancehaving a jet diameter of from about 0.1 mm to about 2 mm (e.g., fromabout 0.2 mm to about 0.5 mm, from about 0.3 mm to about 0.4 mm, fromabout 0.3 mm to about 0.5 mm, about 0.35 mm).

In general, an ingestible device for trans-epithelial delivery isconfigured to provide an internal pressure of at least about 225 psig(e.g., at least about 235 psig, at least about 245 psig, at least about255 psig, at least about 265 psig, at least about 275 psig, at leastabout 285 psig, at least about 295 psig, at least about 305 psig, atleast about 315 psig) and/or at most about 425 psig (e.g., at most about400 psig, at most about 390 psig, at most about 380 psig, at most about375 psig, at most about 370 psig, at most about 360 psig, at most about350 psig, at most about 340 psig, at most about 330 psig). In certainembodiments, an ingestible device for trans-epithelial delivery isconfigured to provide an internal pressure of from about 225 psig toabout 400 psig (e.g., from about 250 psig to about 375 psig, from about300 psig to about 340 psig).

In general, an ingestible device for trans-epithelial delivery isconfigured to have a nozzle pressure at least about 150 psig (e.g., atleast about 175 psig, at least about 200 psig, at least about 210 psig,at least about 220 psig, at least about 225 psig, at least about 230psig, at least about 240 psig, at least about 250 psig, at least about260 psig, at least about 270 psig, at least about 275 psig, at leastabout 280 psig, at least about 290 psig, at least about 300 psig, atleast about 325 psig) and/or at most about 400 psig (e.g., at most about375 psig, at most about 365 psig, at most about 355 psig, at most about350 psig, at most about 345 psig, at most about 335 psig, at most about325 psig, at most about 315 psig, at most about 305 psig). In certainembodiments, an ingestible device for trans-epithelial delivery isconfigured to have a nozzle pressure of from about 150 psig to about 400psig (e.g., from about 150 psig to about 300 psig, from about 180 psigto about 400 psig, from about 190 psig to about 400 psig, from about 200psig to about 400 psig, from about 200 psig to about 375 psig, fromabout 210 psig to about 400 psig, from about 220 psig to about 400 psig,from about 220 psig to about 375 psig, from about 220 psig to about 350psig, from about 225 psig to about 400 psig, from about 225 psig toabout 375 psig, from about 225 psig to about 350 psig, from about 225psig to about 325 psig, from about 230 psig to about 400 psig, fromabout 235 psig to about 250 psig, from about 240 psig to about 400 psig,from about 245 psig to about 400 psig, from about 250 psig to about 400psig, from about 250 psig to about 375 psig, from about 250 psig toabout 350 psig, from about 250 psig to about 325 psig, from about 255psig to about 400 psig, from about 260 psig to about 400 psig, fromabout 265 psig to about 400 psig, from about 270 psig to about 400 psig,from about 275 psig to about 400 psig, from about 275 psig to about 375psig, from about 275 psig to about 350 psig, from about 275 psig toabout 325 psig, from about 280 psig to about 400 psig, from about 280psig to about 320 psig, from about 300 psig to about 375 psig, fromabout 285 psig to about 400 psig, from about 290 psig to about 400 psig,from about 300 psig to about 400 psig, from about 300 psig to about 375psig, from about 300 psig to about 350 psig, from about 300 psig toabout 325 psig, from about 305 psig to about 400 psig, from about 310psig to about 400 psig, from about 315 psig to about 400 psig, fromabout 320 psig to about 400 psig, from about 320 psig to about 375 psig,from about 330 psig to about 400 psig, from about 335 psig to about 400psig, from about 340 psig to about 400 psig, from about 345 psig toabout 400 psig, from about 350 psig to about 400 psig). In someembodiments, an ingestible device for trans-epithelial delivery isconfigured to have a nozzle pressure of between about 220-350 psig(e.g., about 225-350 psig, about 230-350 psig, about 235-350 psig, about240-350 psig, about 245-350 psig, about 250-350 psig, about 255-350psig, about 260-350 psig, about 265-350 psig, about 270-350 psig, about275-350 psig, about 280-350 psig, about 285-350 psig, about 290-350psig, about 300-350 psig, about 220-325 psig, about 225-325 psig, about230-325 psig, about 235-325 psig, about 240-325 psig, about 245-325psig, about 250-325 psig, about 255-325 psig, about 260-325 psig, about265-325 psig, about 270-325 psig, about 275-325 psig, about 280-325psig, about 285-325 psig, about 290-325 psig, about 300-300 psig, about220-300 psig, about 225-300 psig, about 230-300 psig, about 235-300psig, about 240-300 psig, about 245-300 psig, about 250-300 psig, about255-300 psig, about 260-300 psig, about 265-300 psig, about 270-300psig, about 275-300 psig, about 280-300 psig, about 285-300 psig, about290-300 psig, about 220-290 psig, about 225-290 psig, about 230-290psig, about 235-290 psig, about 240-290 psig, about 245-290 psig, about250-290 psig, about 255-290 psig, about 260-290 psig, about 265-290psig, about 270-290 psig, about 275-290 psig, about 280-290 psig, about285-290 psig, about 220-280 psig, about 225-280 psig, about 230-280psig, about 235-280 psig, about 240-280 psig, about 245-280 psig, about250-280 psig, about 255-280 psig, about 260-280 psig, about 265-280psig, about 270-280 psig, about 275-280 psig, about 220-270 psig, about225-270 psig, about 230-270 psig, about 235-270 psig, about 240-270psig, about 245-270 psig, about 250-270 psig, about 255-270 psig, about260-270 psig, about 265-270 psig, about 220-260 psig, about 225-260psig, about 230-260 psig, about 235-260 psig, about 240-260 psig, about245-260 psig, about 250-260 psig, about 255-260 psig, about 220-225psig, about 225-235 psig, about 230-240 psig, about 235-245 psig, about240-250 psig, about 245-260 psig, about 250-265 psig, about 255-270psig, about 260-275 psig, about 265-285 psig, about 270-290 psig, about275-295 psig, about 280-300 psig, about 285-305 psig, about 290-310psig, about 300-315 psig, about 310-320 psig, about 220-230 psig, about220-235 psig, about 220-240 psig, about 220-245 psig, about 220-250psig, about 220-260 psig, about 220-265 psig, about 220-270 psig, about220-275 psig, about 220-285 psig, about 220-290 psig, about 220-295psig, about 220-300 psig, about 220-305 psig, about 220-310 psig, about220-315 psig, about 220-320 psig, about 230-235 psig, about 230-240psig, about 230-245 psig, about 230-250 psig, about 230-260 psig, about230-265 psig, about 230-270 psig, about 230-275 psig, about 230-285psig, about 230-290 psig, about 230-295 psig, about 230-300 psig, about230-305 psig, about 230-310 psig, about 230-315 psig, about 230-320psig, about 240-245 psig, about 240-250 psig, about 240-260 psig, about240-265 psig, about 240-270 psig, about 240-275 psig, about 240-285psig, about 240-290 psig, about 240-295 psig, about 240-300 psig, about240-305 psig, about 240-310 psig, about 240-315 psig, about 240-320psig, about 250-260 psig, about 250-265 psig, about 250-270 psig, about250-275 psig, about 250-285 psig, about 250-290 psig, about 250-295psig, about 250-300 psig, about 250-305 psig, about 250-310 psig, about250-315 psig, about 250-320 psig, about 260-265 psig, about 260-270psig, about 260-275 psig, about 260-285 psig, about 260-290 psig, about260-295 psig, about 260-300 psig, about 260-305 psig, about 260-310psig, about 260-315 psig, about 260-320 psig, about 270-275 psig, about270-285 psig, about 270-290 psig, about 270-295 psig, about 270-300psig, about 270-305 psig, about 270-310 psig, about 270-315 psig, about270-320 psig, about 280-285 psig, about 280-290 psig, about 280-295psig, about 280-300 psig, about 280-305 psig, about 280-310 psig, about280-315 psig, about 280-320 psig, about 290-295 psig, about 290-300psig, about 290-305 psig, about 290-310 psig, about 290-315 psig, about290-320 psig, about 150 psig, about 300 psig, or about 320 psig). Incertain embodiments, an ingestible device for trans-epithelial deliveryhas a nozzle pressure of about 200 psig, about 210 psig, about 220 psig,about 230 psig, about 240 psig, about 250 psig, about 260 psig, about270 psig, about 280 psig, about 290 psig, about 300 psig, about 310 psigor about 320 psig.

Generally, an ingestible device for trans-epithelial delivery isconfigured to contain a dispensable substance at a peak fluid pressureof at least about 150 psig (e.g., at least about 175 psig, at leastabout 200 psig, at least about 210 psig, at least about 220 psig, atleast about 225 psig, at least about 230 psig, at least about 240 psig,at least about 250 psig, at least about 260 psig, at least about 270psig, at least about 275 psig, at least about 280 psig, at least about290 psig, at least about 300 psig, at least about 325 psig) and/or atmost about 400 psig (e.g., at most about 375 psig, at most about 365psig, at most about 355 psig, at most about 350 psig, at most about 345psig, at most about 335 psig, at most about 325 psig, at most about 315psig, at most about 305 psig). In certain embodiments, an ingestibledevice for trans-epithelial delivery is configured to contain adispensable substance at a peak fluid pressure of from about 150 psig toabout 400 psig (e.g., from about 150 psig to about 300 psig, from about180 psig to about 400 psig, from about 190 psig to about 400 psig, fromabout 200 psig to about 400 psig, from about 200 psig to about 375 psig,from about 210 psig to about 400 psig, from about 220 psig to about 400psig, from about 220 psig to about 375 psig, from about 220 psig toabout 350 psig, from about 225 psig to about 400 psig, from about 225psig to about 375 psig, from about 225 psig to about 350 psig, fromabout 225 psig to about 325 psig, from about 230 psig to about 400 psig,from about 235 psig to about 250 psig, from about 240 psig to about 400psig, from about 245 psig to about 400 psig, from about 250 psig toabout 400 psig, from about 250 psig to about 375 psig, from about 250psig to about 350 psig, from about 250 psig to about 325 psig, fromabout 255 psig to about 400 psig, from about 260 psig to about 400 psig,from about 265 psig to about 400 psig, from about 270 psig to about 400psig, from about 275 psig to about 400 psig, from about 275 psig toabout 375 psig, from about 275 psig to about 350 psig, from about 275psig to about 325 psig, from about 280 psig to about 400 psig, fromabout 280 psig to about 320 psig, from about 300 psig to about 375 psig,from about 285 psig to about 400 psig, from about 290 psig to about 400psig, from about 300 psig to about 400 psig, from about 300 psig toabout 375 psig, from about 300 psig to about 350 psig, from about 300psig to about 325 psig, from about 305 psig to about 400 psig, fromabout 310 psig to about 400 psig, from about 315 psig to about 400 psig,from about 320 psig to about 400 psig, from about 320 psig to about 375psig, from about 330 psig to about 400 psig, from about 335 psig toabout 400 psig, from about 340 psig to about 400 psig, from about 345psig to about 400 psig, from about 350 psig to about 400 psig). In someembodiments, an ingestible device for trans-epithelial delivery isconfigured to contain a dispensable substance at a peak fluid pressureof between about 220-350 psig (e.g., about 225-350 psig, about 230-350psig, about 235-350 psig, about 240-350 psig, about 245-350 psig, about250-350 psig, about 255-350 psig, about 260-350 psig, about 265-350psig, about 270-350 psig, about 275-350 psig, about 280-350 psig, about285-350 psig, about 290-350 psig, about 300-350 psig, about 220-325psig, about 225-325 psig, about 230-325 psig, about 235-325 psig, about240-325 psig, about 245-325 psig, about 250-325 psig, about 255-325psig, about 260-325 psig, about 265-325 psig, about 270-325 psig, about275-325 psig, about 280-325 psig, about 285-325 psig, about 290-325psig, about 300-300 psig, about 220-300 psig, about 225-300 psig, about230-300 psig, about 235-300 psig, about 240-300 psig, about 245-300psig, about 250-300 psig, about 255-300 psig, about 260-300 psig, about265-300 psig, about 270-300 psig, about 275-300 psig, about 280-300psig, about 285-300 psig, about 290-300 psig, about 220-290 psig, about225-290 psig, about 230-290 psig, about 235-290 psig, about 240-290psig, about 245-290 psig, about 250-290 psig, about 255-290 psig, about260-290 psig, about 265-290 psig, about 270-290 psig, about 275-290psig, about 280-290 psig, about 285-290 psig, about 220-280 psig, about225-280 psig, about 230-280 psig, about 235-280 psig, about 240-280psig, about 245-280 psig, about 250-280 psig, about 255-280 psig, about260-280 psig, about 265-280 psig, about 270-280 psig, about 275-280psig, about 220-270 psig, about 225-270 psig, about 230-270 psig, about235-270 psig, about 240-270 psig, about 245-270 psig, about 250-270psig, about 255-270 psig, about 260-270 psig, about 265-270 psig, about220-260 psig, about 225-260 psig, about 230-260 psig, about 235-260psig, about 240-260 psig, about 245-260 psig, about 250-260 psig, about255-260 psig, about 220-225 psig, about 225-235 psig, about 230-240psig, about 235-245 psig, about 240-250 psig, about 245-260 psig, about250-265 psig, about 255-270 psig, about 260-275 psig, about 265-285psig, about 270-290 psig, about 275-295 psig, about 280-300 psig, about285-305 psig, about 290-310 psig, about 300-315 psig, about 310-320psig, about 220-230 psig, about 220-235 psig, about 220-240 psig, about220-245 psig, about 220-250 psig, about 220-260 psig, about 220-265psig, about 220-270 psig, about 220-275 psig, about 220-285 psig, about220-290 psig, about 220-295 psig, about 220-300 psig, about 220-305psig, about 220-310 psig, about 220-315 psig, about 220-320 psig, about230-235 psig, about 230-240 psig, about 230-245 psig, about 230-250psig, about 230-260 psig, about 230-265 psig, about 230-270 psig, about230-275 psig, about 230-285 psig, about 230-290 psig, about 230-295psig, about 230-300 psig, about 230-305 psig, about 230-310 psig, about230-315 psig, about 230-320 psig, about 240-245 psig, about 240-250psig, about 240-260 psig, about 240-265 psig, about 240-270 psig, about240-275 psig, about 240-285 psig, about 240-290 psig, about 240-295psig, about 240-300 psig, about 240-305 psig, about 240-310 psig, about240-315 psig, about 240-320 psig, about 250-260 psig, about 250-265psig, about 250-270 psig, about 250-275 psig, about 250-285 psig, about250-290 psig, about 250-295 psig, about 250-300 psig, about 250-305psig, about 250-310 psig, about 250-315 psig, about 250-320 psig, about260-265 psig, about 260-270 psig, about 260-275 psig, about 260-285psig, about 260-290 psig, about 260-295 psig, about 260-300 psig, about260-305 psig, about 260-310 psig, about 260-315 psig, about 260-320psig, about 270-275 psig, about 270-285 psig, about 270-290 psig, about270-295 psig, about 270-300 psig, about 270-305 psig, about 270-310psig, about 270-315 psig, about 270-320 psig, about 280-285 psig, about280-290 psig, about 280-295 psig, about 280-300 psig, about 280-305psig, about 280-310 psig, about 280-315 psig, about 280-320 psig, about290-295 psig, about 290-300 psig, about 290-305 psig, about 290-310psig, about 290-315 psig, about 290-320 psig, about 150 psig, about 300psig, or about 320 psig). In certain embodiments, an ingestible devicefor trans-epithelial delivery is configured to contain a dispensablesubstance at a peak fluid pressure of about 200 psig, about 210 psig,about 220 psig, about 230 psig, about 240 psig, about 250 psig, about260 psig, about 270 psig, about 280 psig, about 290 psig, about 300psig, about 310 psig or about 320 psig.

Generally, an ingestible device for trans-epithelial delivery isconfigured to contain a dispensable substance at a minimum fluidpressure of at least about 50 psig (e.g., at least about 60 psig, atleast about 70 psig) and/or at most about 100 psig (e.g., at most about90 psig, at most about 80 psig). In some embodiments, an ingestibledevice for trans-epithelial delivery is configured to contain adispensable substance at a minimum fluid pressure from about 50 psig toabout 100 psig (e.g., from about 60 psig to about 90 psig, from about 70psig to about 80 psig).

In general, an ingestible device for trans-epithelial delivery isconfigured to have a piston friction of at least about 1 N (e.g., atleast about 2 N, at least about 3 N) and/or at most about 20 N (e.g., atmost about 15 N, at most about 12 N). In certain embodiments, aningestible device for trans-epithelial delivery is configured to have apiston friction of from 1 N to 20 N (e.g., from 2 N to 15 N, from about3N to about 12N).

In general, an ingestible device for trans-epithelial delivery containsthe dispensable substance at an initial fluid volume of at least about50 microliters (μL) (e.g., at least about 100 μL, at least about 150 μL,at least about 200 μL, at least about 250 μL) and/or at most about 800μL (e.g., at most about 700 μL, at most about 600 μL, at most about 500μL, at most about 400 μL). In some embodiments, an ingestible device fortrans-epithelial delivery contains the dispensable substance at aninitial fluid volume of from about 50 μL to about 800 μL (e.g., fromabout 100 μL to about 600 μL, from about 200 μL to about 400 μL).

Generally, an ingestible device for trans-epithelial delivery isconfigured to provide a delivered fluid volume of dispensable substanceof at least about 50 microliters (μL) (e.g., at least about 100 μL, atleast about 150 μL, at least about 200 μL, at least about 250 μL) and/orat most about 800 μL (e.g., at most about 700 μL, at most about 600 μL,at most about 500 μL, at most about 400 μL). In some embodiments, aningestible device for trans-epithelial delivery has a fluid volume ofdispensable substance of from about 50 μL to about 800 μL (e.g., fromabout 50 μL to about 500 μL, from about 100 μL to about 450 μL, fromabout 100 μL, to about 600 μL, from about 200 μL to about 400 μL, fromabout 250 μL to about 400 μL, from about 300 μL to about 400 μL).

In general, an ingestible device for trans-epithelial delivery containsthe dispensable substance at a final fluid volume of at most about 100microliters (μL) (e.g., at least about 90 μL, at least about 80 μL, atleast about 70 μL, at least about 60 μL) and/or at most least 5 μL(e.g., at most about 10 μL, at most about 20 μL, at most about 30 μL, atmost about 40 μL). In some embodiments, an ingestible device fortrans-epithelial delivery contains the dispensable substance at a fluidvolume of from about 30 μL, to about 70 μL (e.g., from about 40 μL, toabout 60 μL, from about 45 μL, to about 55 μL). In general, aningestible device for trans-epithelial delivery is configured todirectly deliver at least about 50% (e.g., at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, at least about 95%,at least about 97%) of the dispensable substance from the ingestibledevice to the submucosa and/or the mucosa (e.g., into the laminapropria).

In general, an ingestible device for trans-epithelial delivery has atleast 1 opening for delivery of dispensable substance (e.g. at least 2openings for delivery of dispensable substance, at least 3 openings fordelivery of dispensable substance, at least 4 openings for delivery ofdispensable substance) and/or most about 8 openings for delivery ofdispensable substance (e.g., at most 7 openings for delivery ofdispensable substance, at most 6 openings for delivery of dispensablesubstance, at most 5 openings for delivery of dispensable substance, atmost 4 openings for delivery of dispensable substance). In certainembodiments, an ingestible device for trans-epithelial delivery has from1 to 8 openings for delivery of dispensable substance (e.g., from 2 to 4openings for delivery of dispensable substance, 2 opening for deliveryof dispensable substance). In some embodiments, an ingestible device fortrans-epithelial delivery has one or more nozzles, with each nozzlehaving a nozzle opening for delivering dispensable substance. In suchembodiments, the ingestible device can have at least 1 nozzle (e.g., atleast 2 nozzles, at least 3 nozzles, at least 4 nozzles) and/or at most8 nozzles (e.g., at most 7 nozzles, at most 6 nozzles, at most 5nozzles, at most 4 nozzles). For example, the ingestible device can havefrom 1 to 8 nozzles (e.g., from 1 to 5 nozzles, from 2 to 4 nozzles, 2nozzles). In embodiments in which an ingestible device fortrans-epithelial delivery includes one or more nozzles, each nozzle canhave a nozzle length of at least about 1 mm (e.g., at least about 2 mm,at least about 3 mm) and/or at most about 5 mm (e.g., at most about 4mm). In some embodiments, each nozzle can have a nozzle length of fromabout 1 mm to about 5 mm. In embodiments in which an ingestible devicefor trans-epithelial delivery includes one or more nozzles, each nozzlecan have a nozzle diameter of at least about 0.1 mm (e.g., at leastabout 0.2 mm, at least about 0.3 mm) and/or at most about 2 mm (e.g., atmost about 1 mm, at most about 0.8 mm, at most bout 0.5 mm, at mostabout 0.4 mm). In some embodiments, each nozzle can have a nozzlediameter of from about 0.1 mm to about 2 mm (e.g., from about 0.1 mm toabout 1 mm, from about 0.15 mm to about 0.5 mm, from about 0.2 mm toabout 0.8 mm, from about 0.25 mm to about 0.45 mm, from about 0.3 mm toabout 0.4 mm, from about 0.3 mm to about 0.5 mm, from about 0.34 mm toabout 0.36 mm, about 0.35 mm). In certain embodiments, each nozzle canhave a nozzle diameter independently selected from the group consistingof about 0.15 mm, about 0.16 mm, about 0.17 mm, about 0.18 mm, about0.19 mm, about 0.20 mm, about 0.21 mm, about 0.22 mm, about 0.23 mm,about 0.24 mm, about 0.25 mm, about 0.26 mm, about 0.27 mm, about 0.28mm, about 0.29 mm, about 0.30 mm, about 0.31 mm, about 0.32 mm, about0.33 mm, about 0.34 mm, about 0.35 mm, about 0.36 mm, about 0.37 mm,about 0.38 mm, about 0.39 mm, about 0.40 mm, about 0.41 mm, about 0.42mm, about 0.43 mm, about 0.44 mm, about 0.45 mm, about 0.46 mm, about0.47 mm, about 0.48 mm, about 0.49 mm, and about 0.50 mm; or moreparticularly, about 0.30 mm, about 0.31 mm, about 0.32 mm, about 0.33mm, about 0.34 mm, about 0.35 mm, about 0.36 mm, about 0.37 mm, about0.38 mm, about 0.39 mm and about 0.40 mm.

In general, an ingestible device for trans-epithelial delivery isconfigured to provide a delivered fluid volume per opening for deliveryof dispensable substance (e.g., per nozzle) of at least about 20microliters (μL) (e.g., at least about 25 μL, at least about μL, atleast about 50 μL, at least about 75 μL, at least about 100 μL) and/orat most about 800 μL (e.g., at most about 700 μL, at most about 600 μL,at most about 500 μL, at most about 400 μL, at most about 300 μL). Insome embodiments, an ingestible device for trans-epithelial delivery isconfigured to provide a delivered fluid volume per opening for deliveryof dispensable substance (e.g., per nozzle) of from about 25 μL to about400 μL (e.g., from about 25 μL, to about 300 μL, from about 100 μL toabout 300 μL).

In one example, an ingestible device with a nozzle having a nozzlediameter of 0.35 mm diameter and containing a dispensable substance at apeak fluid pressure of 150 psig can deliver a jet of the dispensablesubstance at an average jet velocity of about 20 m/s and at an averagejet impact pressure of about 29 psig.

In another example, an ingestible device having a nozzle pressure of 300psig can deliver a dispensable substance at an average jet velocity ofabout 27 m/s and an average jet impact pressure of about 58 psig. Insome embodiments, such an arrangement results in piercing of theintestinal wall.

In another example, an ingestible device having a nozzle with a nozzlediameter of 0.35 mm diameter and containing a dispensable substance at apeak fluid pressure of 320 psig can deliver a jet of the dispensablesubstance having an average jet velocity of about 28 m/s and an averagejet impact pressure of about 62.4 psig.

FIG. 3 shows cross sectional views of a representative ingestible device400 for trans-epithelial delivery, schematically illustrating certainparameters and components of action for the device 400. These include adrive force generator 42 which applies a force (resulting in an internalpressure) to a drive coupling 44. The drive coupling 44 transfers forcefrom the force generator 42 to a fluid volume 46 containing adispensable substance (e.g., a liquid, a suspension). The force appliedto the fluid volume 46 by the drive coupling 44 generates pressure inthe fluid volume 46 (fluid pressure). The pressure in the fluid volume46 generates high-speed flow through an open nozzle 48 to produce a jet50 of fluid at the nozzle outlet 52 that has a nozzle diameter 72 andthe nozzle has a nozzle length 74.

During trans-epithelial delivery, the fluid jet 50 has a jet stablelength 54 that is sufficient for the fluid jet 50 to travel across anozzle stand-off distance 56 to reach the interface of the lumen of theGI tract and the surface of the GI tract facing the lumen. Ultimately,the fluid (e.g., liquid, suspension) impacts the mucosal layer of the GItract (e.g., the epithelial layer and any mucus that may be present onthe epithelial layer) as a stable stream of fluid with little breakupinto a spray and is deposited in the submucosal and/or the mucosaltissue 58. That is, between the nozzle outlet 52 and the site of impactat the mucosa, the jet 50 has a jet diameter 76 that can vary in themanner discussed above with respect to the average jet diameter.

The fluid volume 46 experiences a peak fluid pressure 60 that generatesthe fluid jet 50 that exits the device 40 with a peak jet velocity, andimpacts the interface of the lumen of the GI tract and the surface ofthe GI tract facing the lumen with a peak jet power, peak jet pressureand peak jet force. One of ordinary skill in the art recognizes thatthese three parameters are interconnected.

The pressure in the fluid volume 46 decreases during delivery so thatthe fluid pressure during delivery 70 varies, as does the jet power, jetforce, and jet pressure. The fluid pressure during delivery 70 maintainsthe fluid jet 50 at sufficient jet impact force during delivery tocontinue fluid (dispensable substance including one or more therapeuticagents) delivery from the fluid volume 46 into the submucosal and/ormucosal tissue 58. The surrounding tissue can then absorb the deliveredtherapeutic agents for systemic delivery of the therapeutic agent.

Even prior to when the subject swallows the ingestible device, the drivecoupling 44 transmits force from the force generator 42 to the fluidvolume 46. The drive coupling 44 is prevented from moving by arestraining mechanism 80 (e.g., a pin or plug that selectively degradesand/or selectively erodes) until movement of the drive coupling istriggered by a triggering mechanism, and/or an opening becomes open.

FIGS. 4A-5B show cross sections of an example ingestible device 100.

FIG. 4A shows an exterior view of the ingestible device 100. The device100 is generally cylindrical with a longitudinal axis and a generallysmooth exterior surface 102. The exterior surface 102 includes a bottomhousing 104 with an inlet 106 at one end, and a slider 108 (showntransparent) at the opposite end from the inlet 106 (e.g., apressurization inlet port). The device 100 is a purely mechanical devicefor the delivery of a therapeutic agent to the GI tract, and does notcontain any electronics.

FIG. 4B shows an embodiment of the device 100. The device 100 includes agas reservoir 112, a dispensable substance reservoir 114 that containsthe substance to be dispensed (e.g., a pharmaceutical formulation), aslider 108, degradable and/or erodible elements 116 (e.g., shear pins),and structural elements 118 (e.g., structural shear pins). In general,the degradable and/or erodible elements 116 are configured to degradeand/or erode under certain conditions, while the structural elements 118are configured to provide additional mechanical strength beyond thatprovided by the degradable and/or erodible elements 116. Together, thedegradable and/or erodible elements 116 and structural elements 118 areable to hold back the force of the force generator (e.g., a pressurizedgas within the gas reservoir 112). However, when the degradable and/orerodible elements 116 begin to or completely degrade and/or erode in thepresence of GI fluid, the structural elements 118 cannot alone hold backthe force of the force generator (e.g., the pressurized gas), and theslider 108 moves to the open position. In some embodiments, thedegradable and/or erodible elements 116 and structural elements 118 areplaced in pairs with like elements on opposite sides of the device. Insome embodiments, the degradable and/or erodible elements 116 are madeof an enteric material. For example, the enteric material may bedegradable and/or erodible in the small intestine of the GI tract, orthe enteric material may be degradable and/or erodible in the largeintestine of the GI tract, such as the colon. Although shown in FIGS.2A-4B as including both the degradable and/or erodible elements 116 andthe structural elements 118, in some embodiments, the device 100includes the degradable and/or erodible elements 116 but does notinclude the structural elements 118.

FIGS. 4A-5B show cross sections of an embodiment of the device 100,which includes gas reservoir 112, a dispensable substance reservoir 114that contains the substance to be dispensed (e.g., a pharmaceuticalformulation), a slider 108, degradable and/or erodible elements 116(e.g., shear pins), and structural elements 118 (e.g., structural shearpins). In general, the degradable and/or erodible elements 116 areconfigured to degrade and/or erode under certain conditions, while thestructural elements 118 are configured to provide additional mechanicalstrength beyond that provided by the degradable and/or erodible elements116. Together, the degradable and/or erodible elements 116 andstructural elements 118 are able to hold back the force of the forcegenerator (e.g., a pressurized gas within the gas reservoir 112).However, when the degradable and/or erodible elements 116 begin to orcompletely degrade and/or erode in the presence of GI fluid, thestructural elements 118 cannot alone hold back the force of the forcegenerator (e.g., the pressurized gas), and the slider 108 moves to theopen position. In some embodiments, the degradable and/or erodibleelements 116 and structural elements 118 are placed in pairs with likeelements on opposite sides of the device. In some embodiments, thedegradable and/or erodible elements 116 are made of an enteric material.For example, the enteric material may be degradable and/or erodible inthe small intestine of the GI tract, or the enteric material may bedegradable and/or erodible in the large intestine of the GI tract, suchas the colon. Although shown in FIGS. 2A-4B as including both thedegradable and/or erodible elements 116 and the structural elements 118,in some embodiments, the device 100 includes the degradable and/orerodible elements 116 but does not include the structural elements 118.

As shown in FIGS. 4A-5B, the ingestible device 100 is encased by acoating 120, such as a degradable and/or erodible coating, for example,an enteric coating, that covers the exterior surface 102. Optionally,the ingestible device 120 does not include the coating 120. Further, incertain embodiments, only certain portions of the ingestible device 100include the coating 120. As an example, in some embodiments, only thepockets 124 (described below) are coated, e.g., coated with a degradableand/or erodible material, for example, an enteric material.

FIGS. 4B and 4C show the device 100 in its open position, where thesubstance reservoir 114 is fluidly connected to the outside of thedevice via the nozzles 122 (visible in FIG. 3C). To prepare the devicefor use, the dispensable substance (e.g., a therapeutic agent or apharmaceutical formulation containing a therapeutic agent) is loadedinto the substance reservoir 114 via the nozzles 122 with the device inthis open position. Once the dispensable substance is loaded into thesubstance reservoir 114, the slider 108 is shut by sliding it axially,disconnecting the nozzles 122 from the exterior of the device so thatthe device 100 is in its closed position. Note that the location of thestructural elements 118 and elements 116 are depicted in FIGS. 4B and 4Cas these elements are not yet on the device 100 while it is in the openposition depicted. The device 100 may also include a guide pin thatprovides alignment of nozzles 122 to the hole provided by the slider108, and may also prevent the slider from continuing to translateaxially.

FIGS. 5A and 5B show the device in its closed position in which theslider 108 is held in place by a number of elements 116 and 118 thatmate with pockets (e.g., pin pockets) 124. The location of elements 116extend through the housing at the positions indicated while the device100 is in the closed position. A single nozzle 122 is shown in the viewof FIG. 5A and two nozzles are shown in the view of FIG. 5B. One or moretop housing seals (e.g., sealing O-rings) 126 assist in containing thedispensable substance behind the slider 108 so that the dispensablesubstance does not leak to the environment external to the device 100. Apiston (e.g., substance/gas piston) 130 and a seal (e.g., sealingO-ring) 132 assist in separating the gas in the gas reservoir 112 fromthe dispensable substance in the substance reservoir 114. The piston 130surrounds the gas reservoir 112 and is configured to slide axiallywithin the bottom housing 104. In some embodiments, the slider 108 isnot an external sliding mechanism as shown, but is an internal slider.

With the dispensable substance loaded within the substance reservoir114, the slider 108 is held in place with respect to the top housing 134with the elements 116 and structural elements 118 within the pockets124. The pockets 124 each have a through-portion 124A piercing theslider 108, and a blind hole portion 124B within the top housing 134. Inthe closed position (FIGS. 5A and 5B), the through-portion 124A and theblind hole portion 124B of each of the pockets 124 align, allowing theelements 116 and/or 118 to be inserted through the slider 108 and fastenit to the top housing 134. Once in this fixed position, the gasreservoir 112 is charged with pressurized gas up to a predeterminedpressure (e.g., about 300 psig) via the inlet 106. The inlet 106includes a valve 128 that allows gas to flow into the gas reservoir 112,but prevents the pressurized gas from travelling back out through theinlet 106. In general, any appropriate valve may be used. Examples ofvalves include check valves, ball check valves, umbrella valves,duckbill valves, or the like. In some embodiments, the valve 128 isreplaced by a static plug (e.g., an adhesive applied to the inlet 106)that can withstand the pressure of the pressurized gas reservoir 112.

The elements 116 and 118 are generally made of materials and are sizedand shaped such that they, in combination, provide enough rigidity tohold the slider 108 in the closed position under the internal pressureof the pressurized air in the gas reservoir 112, e.g., in the range ofabout 150-400 psig. Upon dissolution, degradation and or erosion of theelements 116, the maximum pressure that the remaining structuralelements 118 can withstand without breaking drops below the internalpressure within the gas reservoir 112. In some embodiments, thestructural elements 118 are made from a relatively brittle material, andthereby fail and release the slider 108 and allow the dispensablesubstance to forcefully leave the device via the nozzles 122. AlthoughFIGS. 4A-5B show a single element 116 and a single element 118, thedisclosure is not limited in this sense. For example, the device 100 caninclude more than one (e.g., two, three, four, etc.) elements 116,and/or more than one (e.g., two, three, four, etc.) elements 118. Insome embodiments, there is an even number of elements 116 and ofstructural elements 118, and the elements 116 and 118 are arranged in analternating configuration around the longitudinal axis of the device100. In other embodiments, there is an even number of elements 116 andof structural elements 118, and the elements 116 and 118 are arrangedsuch that elements 116 are opposite other elements 116 and structuralelements 118 are opposite other structural elements 118 around thelongitudinal axis of the device 100. In certain embodiments, elements116 and 118 are co-located within the same pocket 124 and may comprise amatrix of materials such as 118 consisting of fibers, or consisting of acoaxial pin 118 surrounded by an annulus of element 116. In someembodiments, the coating 120 may be placed only in the region of theelements 116 and/or 118, e.g., in an annulus. Alternatively, entericmaterial may be in the pocket portions 124A and/or 124B as a plugseparating the elements 116 and/or 118 from the exterior environment.

The properties of the elements 116 can be varied to select the desiredperformance. For example, their effective force-restraining area can beincreased by increasing the diameter and thus the cross section of eachelement 116, and/or by increasing the number of the elements 116.Increasing the area allows for a safety factor to permit longer periodsof storage and shipping, variation in dissolvability, degradability andor erodability between batches of elements 116 and/or 118, andvariations in the pressure within the gas reservoir 112, or the like. Insome embodiments, elements 116 and 118 are pins having a diameter ofabout 0.9 mm, but can be thinner (e.g., about 0.8 mm) or wider.

In some embodiments, the elements 116 and/or the structural elements 118have configurations other than straight pins. For example, one or moreelements 116 can be an annular member that fits within a grooved pocket(rather than the discrete pockets 124 shown) that encircles thecircumference of the slider 108. The element(s) can be cotters, shearpins, linchpins, split pins, straight pins, dowels, biscuits, clasps,clamps, flanges, rivets, or the like. In some embodiments one or more ofthe elements 116 is a restraining device other than a pin, such as aclamp, a spacer, or the like.

The gas reservoir 112 contains pressurized gas. In some embodiments, thegas is air, however gases other than air are possible. Nonlimitingexamples of compressed gases include, nitrogen (N₂), oxygen (O₂), argon(Ar), krypton (Kr), helium (He) or other inert or noble gases that donot interact or are compatible with the GI tract, with preference tohigher molecular weight gasses that would decrease any permeation of thedrive gas out of the device and therefore increase shelf life. In someembodiments, the gas is carbon dioxide (CO₂).

The device 100 maintains a gas/fluid barrier internally, and the gasreservoir 112 can keep pressurized gas from interacting with a fluiddispensable substance (e.g., dispensable substance in the substancereservoir 114). The substance reservoir 114 may have a residual volumeof <0.050 mL after the dispensing period is complete, and does notinduce agglomeration that would prevent therapeutic agent delivery.

The device 100 also can have several characteristics that make it safeto be stored and transported before being swallowed by a patient. Thedevice 100 can maintain an internal pressure of about 350 psig over theshelf life of the device, e.g., hold a pressure of about 350 psig forabout 6 months. The dispensable substance-contacting substance reservoir114 does not have an effect on the therapeutic agent contained within,and the device and the therapeutic agent are not affected (in efficacy,safety, consistency, or bioavailability) by each other during devicestorage, transit, and dispensing (e.g., with a storage time up to aboutsix months, or up to about 12 months). The substance reservoir 114 canresist contamination from outside sources prior to dispensing.

In some embodiments, as shown in FIG. 6, the diameter of a nozzle asmeasured at the point of interface with the dispensable substancereservoir can be the same as, smaller than, or larger than the diameteras measured at the nozzle opening (location of delivery of thedispensable substance from the ingestible device). Table 1 providesnozzle diameter (in millimeters) and nozzle length (in millimeters) forthe nozzle designs shown in FIG. 6.

TABLE 1 FIG. 6 Nozzle diameter Nozzle length A 0.35 0.5 B 0.35 0.5 C0.35 1.5 D 0.35 1.5 E 0.35 1 F 0.35 1 G 0.5 0.5 H 0.5 0.5 I 0.5 1.5 J0.5 1.5 K 0.5 1

In some embodiments, a tapered nozzle may exhibit enhanced jettingproperties. In certain embodiments, a non-tapered nozzle relatively maybe relatively inexpensive and simple to manufacture. In someembodiments, a small reducing in certain jet properties with arelatively simplified (e.g., non-tapered) nozzle can be compensated withvariation of more easily controlled parameters such as the internalpressure and/or fluid pressure. In some embodiments where the jetexhibits turbulent flow, considering the variations in the flow profilewhich is inherent to the turbulent nature of the flow, and small impactsof nozzle length variations on the jet velocity, the length of thenozzle may be selected based on mechanical design constraints andrequired thickness of the ingestible devices.

In some embodiments, a smaller nozzle diameter (e.g., about 0.35millimeter) is can result in longer dispensing time (˜120 milliseconds),which can better align with achievable opening times of ˜10 millisecondsand higher velocity for a given peak internal pressure. In someembodiments, a smaller nozzle diameter can also provide actualdispensing times and jet velocities that are closer to the predictedvalues.

FIG. 6 shows exemplary cross sections of the nozzles 122 within theslider 108 (although nozzles depicted in FIG. 6 may be used in one ormore of other embodiments of ingestible devices disclosed herein). Insome embodiments, the nozzles are about 0.15-0.5 mm in diameter andabout 0.3-1.5 mm in length. The throat (e.g., the narrowing portion) ofthe nozzle can be rounded (as in the top right) or sharp (as in thebottom left) and the neck can have varying lengths. Each of theseparameters have an effect on the jet(s) generated by the nozzle,modulating, for example, average jet diameter, jet velocity, peak jetpower, peak jet pressure, peak jet force, and average dispensing time.These characteristics can affect the efficacy of delivery and/or subjectuptake of the therapeutic agent.

FIG. 7 shows a histologic example of a jetted fluid in situ. This resultwas achieved with a 0.35 mm nozzle and jetting pressure of 250 psig, andan estimated 181 μL bolus volume. The fluid passed through the mucosaand is within the submucosal region. In this example, the complete boluswas not delivered, possibly due to the physical volume constraints ofthe region. This indicates that multiple nozzles each delivering asmaller bolus of therapeutic agent may be preferred to maximize thebioavailability of the therapeutic agent.

Referring back to FIGS. 4A-5B, the ingestible device 100 has atriggering mechanism that causes the device 100 to release thedispensable substance within the substance reservoir 114 when theingestible device reaches the desired location within the GI tract. Thetrigger that initiates dispensable substance release can have two parts:the enteric coating 120 enrobing the exterior surface 102 of the device100, and the elements 116. The elements 116 are either covered with anenteric coating or are themselves are made of an enteric material. Theenteric material may be degradable and/or erodible in the smallintestine of the GI tract, or may be degradable and/or erodible in thelarge intestine of the GI tract, for example, the colon. Such atwo-stage release mechanism allows the device 100 to transit through theGI tract to the desired location intact before releasing the therapeuticagent.

In the first stage, the enteric coating 120 dissolves, degrades and/orerodes while the device 100 is within a desired portion of the GI tract,e.g., the small intestine or the large intestine. The enteric coating120 is chosen such that it is stable in the acidic environment of thestomach and dissolves, degrades and/or erodes only when exposed to themore neutral environment of the small intestines (e.g., pH>5) or theslightly acidic to neutral environment of the large intestine (e.g., pH5.5-7). The thickness of the coating 120 is chosen such that itdissolves, degrades and/or erodes (either entirely, or enough to exposethe elements 116) when the swallowed device 100 is predicted to havetransited through the stomach and be within the small intestine or largeintestine.

Once the enteric coating 120 has dissolved, degraded and/or eroded fromthe exterior surface 102 of the device 100, the elements 116 of thedevice 100 are exposed to the GI tract. The elements 116 are configuredto dissolve, degrade and/or erode upon exposure to the environment ofthe small intestine (e.g., a water soluble material). Generally, theelements 116 dissolve, degrade and/or erode more rapidly than does theenteric coating 120. The elements 116 can dissolve, for example, withinabout 1 minute of the enteric coating 120 dissolving, degrading and/oreroding and exposing the elements 116 to the small intestineenvironment, compared to, for example, about 30 minutes for the entericcoating 120 to degrade. It is not necessary that the enteric coating 120dissolves, degrades and/or erodes in its entirety. As the entericcoating 120 starts to degrade water or other luminal contents may passthrough it and cause the elements 116 to dissolve and thereby lose theirmechanical holding strength.

Materials for the elements 116 can be isomalt, sugars like maltose orsucrose, or degrading materials of different sorts.

The elements 116 and the structural elements 118 can be made ofmaterials and are sized and shaped such that they, in combination,provide enough rigidity to hold the slider 108 in the closed positionunder the pressure of the pressurized gas in the gas reservoir 112,which can be in the range of 150-400 psig. For example, if the gasreservoir 112 is to be pressurized to 260 psig, the elements 116 and thestructural elements 118 can be designed to hold back 300 psig ofpressure. In one arrangement, the retaining strength of the elements 116is 80 psig, and the retaining strength of the structural elements 118 is220 psig. Upon dissolution, degradation and/or erosion of the elements116, the structural elements 118 are exposed to the pressure of 260 psigwithin the gas reservoir 112. As the 260 psig within the gas reservoir112 exceeds the reduced restraining strength of 220 psig, the remainingstructural elements 118 break. The combination of the dissolution,degradation and/or erosion of the elements 116 followed by the breakingof the structural elements 118 releases the slider 108.

In some embodiments, the elements 116 and the structural elements 118are made of the same material. The elements 116 have a smaller crosssectional area than the structural elements 118 and thus fail morequickly than the structural elements 118. In other embodiments, theelements 116 and the structural elements 118 are made of differentmaterials, where the structural elements 118 are stronger but morebrittle than the elements 116.

In some embodiments, only elements 116 are present, without structuralelements 118. In such instances, the elements 116 are configured tobreak and release the piston 130 and slider 108 in a single step(following dissolving, degrading and/or eroding of the enteric coating120).

To dispense the therapeutic agent, the device 100 moves from the closedposition in FIGS. 5A and 5B back to the open position of FIGS. 3B and 3Cwhere the substance reservoir 114 is fluidly connected to the outside ofthe device (in this instance, with the GI tract). Once the shear pinsdissolve/degrade/erode and/or are sheared, the piston 130 is released toslide axially within the bottom housing 104, and the slider 108 slidesrelative to the top housing 134. The motion of the slider 108 positionsthe nozzles 122 such that the portion of the nozzles 122 within the tophousing 134 aligns with the fluid outlet portion of the nozzles 122within the slider 108. The movement of the piston 130, driven by thenow-unrestrained pressure within the air reservoir 122, forces thetherapeutic within the substance reservoir 114 out through the nozzles122. The elements 116 and 118 may remain only in the blind hole portion124B of the pockets 124. In some embodiments, the dispensing time isapproximately 120 ms. In some embodiments, the time for the slider 108to move from the closed to the open position is approximately 10 ms.

FIG. 8 shows an exemplary process flow chart 800 for use of aningestible device in which pressure is applied to the dispensablesubstance before the subject swallows the ingestible device. The processbegins at step 802, when the patient swallows the ingestible device. Instep 804, a triggering condition (e.g., pH, change in pH, presence ofcertain enzyme, concentration of certain enzyme) is met in the GI tract,thereby triggering the release mechanism. In step 806, the releasemechanism actuates the delivery mechanism at the intended location ofthe GI tract, whereby the opening(s) of the ingestible device becomeopen. In step 808, force applied to the dispensable substance by thedrive mechanism generates high-speed flow of the dispensable substancethrough the opening(s) in the ingestible device, resulting in deliveryof a jet of the dispensable substance from the ingestible device foreach opening. In step 810, the jet has a sufficient jet stable lengthfor the jet to impact the GI tissue of the subject. In step 812, thepeak jet power of the jet is sufficient to achieve trans-epithelialdelivery of the therapeutic agent contained in the dispensablesubstance. In step 814, the fluid pressure of the dispensable substancedecreases during delivery but is sufficiently so that the peak jet powercontinues to be sufficient to achieve trans-epithelial delivery of thetherapeutic agent contained in the dispensable substance.

FIG. 9A shows an embodiment of an ingestible device 900 fortrans-epithelial delivery. The device 900 includes housing parts 902Aand 902B, a fluid volume 904 containing a dispensable substance, nozzles906 with nozzle openings 908, pressurized gas as a drive force generator910, a drive coupling 912 with an O-ring 913 seal, a ring 914 and avalve 915 (inlet for compressed gas). Similar to the device shown inFIGS. 4A-5B, when the device 900 is swallowed by the subject, thedispensable substance in the device is already pressurized. However, thering 914 prevents the pressure of the drive force generator 910 and thedrive coupling 912 from forcing the dispensable substance in the fluidvolume 904 through the nozzle openings 908. When the device 900 reachesthe appropriate location in the GI tract, the ring 914 erodes, degradesand/or dissolves. Thus, the pressure of the drive force generator 910and the drive coupling 912 is applied to the dispensable substance 904,forcing the cap to move to expose openings 908. As shown in FIG. 9B, thehousing part 902B has a slot 903 into which a portion of housing part902A fits such that the motion of the housing part 902A is both axialand rotational (e.g., a track and cam arrangement). This arrangement canresult in relatively reduced axial movement of the housing part 902Bduring delivery of the dispensable substance, which can result inmaintenance of a relatively high internal pressure during delivery ofthe dispensable sub stance.

FIG. 10A shows an embodiment of an ingestible device 1000 fortrans-epithelial delivery. FIG. 10B is an exploded view of theingestible device 1000. The ingestible device 1000 has housing parts1002A and 1002B, a fluid volume 1004 containing a dispensable substance,nozzles 1006, nozzle openings 1008, parallel springs 1010A and 1010B, apiston 1012, a pin 1014, a pin 1016, a spring 1018 and a cap 1020.Similar to the device shown in FIGS. 4A-5B, when the device 1000 isswallowed by the subject, the dispensable substance in the device isalready pressurized. However, the pins 1014 and 1016 prevent thepressure of the springs 1010A and 1010B and the piston 1012 from forcingthe dispensable substance in the fluid volume 1004 through the nozzleopenings 1008. When the device 1000 reaches the appropriate location inthe GI tract, the pin 1014 erodes, degrades and/or dissolves, and thepin 1016 is not sufficient to hold back the pressure from the springs1010A and 1010B and the piston 1012. Thus, the pressure of the springs1010A an 1010B and the piston 1012 is applied to the dispensablesubstance, forcing the spring 1020 to quickly move the cap 1018 forward.This rapidly exposes the nozzle openings 1008 to the environmentexterior to the device 1000 so that the dispensable substance isdelivered out of the openings 1008 in the form of a jet. This results inin trans-epithelial delivery of the therapeutic agent contained in thedispensable substance. In some embodiments, the housing of theingestible device 1000 has a diameter of about 11 mm, a length of about26 mm, a wall thickness of about 0.8 mm, an end round of about 1.5 mmand an internal volume of about 1685 μL. In such embodiments, the fluidvolume 1004 can be about 325 μL.

FIG. 10C shows aspects of steps in assembling the ingestible device1000. In step 1020, the cap 1020 and spring 1018 are combined with thehousing part 1002B and pins 1014 and 1016, and this module issterilized. In step 1022, the dispensable substance 1004 is disposed inthe housing part 1002B in an aseptic environment and then sealed withinthe housing part 1002B via the piston 1012. In step 1024, the housingpart 1002A and its components are assembled in a clean environment. Instep 1026, the resulting modules are joined together in a cleanenvironment to compress the springs 1010A and 1010B to provide theingestible device 1000. As shown in step 1026, the assembly process caninclude using a jig to hold the housing part 1002A to preventover-loading of the cap 1020/spring 1018/pin 1014/pin 1016 combination.

FIG. 10D shows an embodiment of an ingestible device 10001 fortrans-epithelial delivery. The ingestible device 10001 has housing parts1002A1 and 1002B1, a fluid volume 10041 containing a dispensablesubstance, nozzles 10061, nozzle openings 10081, parallel springs 1010A1and 1010B1, a piston 10121, a pin 10141, a pin 10161, a spring 10181 anda cap 10201. Similar to the device shown in FIGS. 4A-5B, when the device10001 is swallowed by the subject, the dispensable substance in thedevice is already pressurized. However, the pins 10141 and 10161 preventthe pressure of the springs 1010A1 and 1010B1 and the piston 10121 fromforcing the dispensable substance in the fluid volume 10041 through thenozzle openings 10081. When the device 10001 reaches the appropriatelocation in the GI tract, the pin 10141 erodes, degrades and/ordissolves, and the pin 10161 is not sufficient to hold back the pressurefrom the springs 1010A1 and 1010B1 and the piston 10121. Thus, thepressure of the springs 1010A1 an 1010B1 and the piston 10121 is appliedto the dispensable substance, forcing the spring 10201 to quickly removemove the cap 10181 forward. This rapidly exposes the nozzle openings10081 to the environment exterior to the device 10001 so that thedispensable substance is delivered out of the openings 10081 in the formof a jet. This results in in trans-epithelial delivery of thetherapeutic agent contained in the dispensable substance. In someembodiments, the spring force of the spring 10181 has a force of about30 Newtons, the parallel springs 1010A1 and 1010B1 have a force of 110Newtons to provide an internal pressure of about 320 psig with about 50Newtons of force at the end of the stroke, and the fluid volume 10041 isabout 225 μL. In some embodiments, the housing of the ingestible device10001 has a diameter of about 11 mm, a length of about 26 mm, a wallthickness of about 0.8 mm, an end round of about 5.5 mm (spherical) andan internal volume of about 1475 μL. In such embodiments, the fluidvolume 10041 can be about 225 μL.

FIG. 10E shows an embodiment of an ingestible device 10002 fortrans-epithelial delivery. The ingestible device 10002 has housing parts1002A2 and 1002B2, a fluid volume 10042 containing a dispensablesubstance, nozzles 10062, nozzle openings 10082, parallel springs 1010A2and 1010B2, a piston 10122, a pin 10142, a pin 10162, a spring 10182 anda cap 10202. Similar to the device shown in FIGS. 4A-5B, when the device10002 is swallowed by the subject, the dispensable substance in thedevice is already pressurized. However, the pins 10142 and 10162 preventthe pressure of the springs 1010A2 and 1010B2 and the piston 10122 fromforcing the dispensable substance in the fluid volume 10042 through thenozzle openings 10082. When the device 10002 reaches the appropriatelocation in the GI tract, the pin 10142 erodes, degrades and/ordissolves, and the pin 10162 is not sufficient to hold back the pressurefrom the springs 1010A2 and 1010B2 and the piston 10122. Thus, thepressure of the springs 1010A2 an 1010B2 and the piston 10122 is appliedto the dispensable substance, forcing the spring 10202 to quickly removemove the cap 10182 forward. This rapidly exposes the nozzle openings10082 to the environment exterior to the device 10002 so that thedispensable substance is delivered out of the openings 10082 in the formof a jet. This results in in trans-epithelial delivery of thetherapeutic agent contained in the dispensable substance. In someembodiments, the spring force of the spring 10182 has a force of about12 Newtons, the parallel springs 1010A2 and 1010B2 have a force of 58Newtons to provide an internal pressure of about 320 psig with about 25Newtons of force at the end of the stroke, and the fluid volume 10042 isabout 120 μL. In some embodiments, the housing of the ingestible device10002 has a diameter of about 8.5 mm, a length of about 23.3 mm, a wallthickness of about 0.75 mm, an end round of about 4.25 mm (spherical)and an internal volume of about 775 μL. In such embodiments, the fluidvolume 10042 can be about 120 μL.

FIG. 11 shows an ingestible device 1100 which includes a housing 1102, afluid volume 1104, a liquid-gas reservoir (drive force generator) 1106,a drive coupling 1108, a seal 1109, a pin 1114 and a pin 1116. Theingestible device 1100 is configured so that, before the subjectswallows the device, the dispensable substance in fluid volume 1104 isunder pressure from the liquid-gas reservoir 1106 via the drive coupling1108, but the pins 1114 and 1116 prevent the dispensable substance influid volume 1004 from being delivered from the device 1100 vianozzle(s) with nozzle opening(s) (not shown). When the device 1100reaches the appropriate location in the GI tract, the pin 1114 erodes,degrades and/or dissolves (e.g., due to pH, change in pH, presence ofcertain enzyme, and/or concentration of certain enzyme), and the pin1116 is no longer sufficient to hold back the pressure from theliquid-gas reservoir 1106 and the drive coupling 1108. Thus, thispressure is applied to the dispensable substance in the fluid volume1104, forcing the dispensable substance out of the nozzle openings (notshown) in the form of a jet. This results in in trans-epithelialdelivery of the therapeutic agent contained in the dispensable substance.

FIG. 12 shows an ingestible device 1200 which includes a first housingpart 1202A, a second housing part 1202B, a fluid volume 1204, a driveforce generator 1206, nozzles 1208 with nozzle openings 1210, plugs1212, a seal 1214, a seal 1216 and a membrane 1218. The ingestibledevice 1200 is configured so that, before the subject swallows thedevice, the dispensable substance in fluid volume 1204 is under pressurefrom the drive force generator 1206, but the plugs 1212 prevent thedispensable substance in fluid volume 1204 from being delivered from thedevice 1200 via nozzle openings 1210. When the device 1200 reaches theappropriate location in the GI tract, the plugs 1212 erode, degradeand/or dissolve (e.g., due to pH, change in pH, presence of certainenzyme, and/or concentration of certain enzyme), so that the pressurefrom the drive force generator 1206 breaks the seal 1216 (made of arelatively low mechanical strength material, such as a seal), whichcauses the membrane 1218 to expand into the fluid volume 1204, forcingthe dispensable substance out of the nozzle openings 1210 in the form ofa jet. This results in in trans-epithelial delivery of the therapeuticagent contained in the dispensable substance.

The housing parts 1202A and (including the membrane 1218) are initiallyseparate from each other. The plugs are disposed in the nozzles 1210,the dispensable substance is disposed in the fluid volume 1204, and theseal 1216 is added. The dispensable substance (including the therapeuticagent) is first sterilized, and then disposed in the fluid volume 1204under aseptic conditions. The drive force generator 1206 is manufacturedin a clean environment and then incorporated with the housing part1202B, after which the membrane 1218 is added. Subsequently, the housingparts 1202A and 1202B are joined in a clean environment to produce theingestible device 1200.

FIG. 13 shows an embodiment of an ingestible device 1300 fortrans-epithelial delivery. The device 1300 has a housing 1302 with afluid volume 1304 containing a dispensable substance, nozzles 1306,nozzle openings 1308, a tensioned spring 1310, a drive force generator1312, a band 1314 around the device, a seal 1315, a cap 1318, a membrane1317 and a seal 1320. When the device 1300 is swallowed by the subject,the dispensable substance in the device is already pressurized. However,the band 1314 prevents the pressure of the drive force generator 1312from relieving the tension in the spring 1310 so that the dispensablesubstance in the fluid volume 1304 is prevented from going through thenozzle openings 1308. When the device 1300 reaches the appropriatelocation in the GI tract, the band 1314 erodes, degrades and/ordissolves. Thus, the tension in the spring 1310 is relieved, and thespring moves to where the band 1314 was located, thereby rapidlyexposing the nozzle openings 1308 to the environment exterior to thedevice 1300 so that the dispensable substance is delivered out of theopenings 1308 in the form of a jet. This results in in trans-epithelialdelivery of the therapeutic agent contained in the dispensablesubstance.

FIG. 14 shows an embodiment of an ingestible device 1400 fortrans-epithelial delivery. The device 1400 has a housing 1402 with afluid volume 1404 containing a dispensable substance, a membrane 1405defining the fluid volume 1404, an opening 1407 leading to nozzles 1406,nozzle openings 1408, a tensioned spring 1410, a pressurized gas (driveforce generator) 1412, a band 1414, a cap 1418 and a seal 1420. When thedevice 1400 is swallowed by the subject, the dispensable substance inthe device is already pressurized. However, the band 1414 keeps thespring 1410 tensioned so that the dispensable substance in the fluidvolume 1404 is prevented from going through the nozzle openings 1408.When the device 1400 reaches the appropriate location in the GI tract,the band 1414 erodes, degrades and/or dissolves, relieving the tensionin the spring 1410, which moves to where the band 1414 had been located,thereby rapidly exposing the nozzle openings 1408 to the environmentexterior to the device 1400 so that the dispensable substance isdelivered out of the openings 1408 in the form of a jet. This results inin trans-epithelial delivery of the therapeutic agent contained in thedispensable substance.

In some embodiments, the dispensable substance is not under pressurewhen the subject swallows the ingestible device. The following areillustrative examples of such ingestible devices.

As an example, FIG. 15A shows an embodiment of an ingestible device 1500for trans-epithelial delivery. FIG. 15B shows an exploded view of theingestible device 1500. The ingestible device 1500 has housing parts1502A and 1502B, a fluid volume 1504 containing a dispensable substance,nozzles 1506, nozzle openings 1508, parallel springs 1510A and 1510B, aplunger 1511, a piston 1512, a piston 1513, a pin 1514 and a pin 1516.When the device 1500 is swallowed by the subject, the pins 1514 and 1516prevent the dispensable substance in fluid volume 1504 from being underpressure from the springs 1510A and 1510B, the plunger 1511 and thepiston 1512. Thus, the pins 1514 and 1516 prevent the pressure of thesprings 1510A and 1510B, the plunger 1511 and the piston 1512 fromforcing the dispensable substance in the fluid volume 1504 through theopenings 1508. When the device 1500 reaches the appropriate location inthe GI tract, the pin 1514 erodes, degrades and/or dissolves (e.g., dueto pH, change in pH, presence of certain enzyme, and/or concentration ofcertain enzyme), and the pin 1516 is no longer sufficient to hold backthe pressure from the springs 1510A and 1510B, the plunger 1511 and thepiston 1512. Thus, the pressure of the springs 1510A and 1510B, theplunger 1511 and the piston 1512 is applied to the dispensable substancein the fluid volume 1504, forcing the dispensable substance out of thenozzle openings 1508 in the form of a jet. This results in intrans-epithelial delivery of the therapeutic agent contained in thedispensable substance.

FIG. 15C shows aspects of a process of assembling the ingestible deviceof 1500. In steps 1520 and 1522, the housing part 1502B and piston 1513are combined and sterilized, the dispensable substance 1504 is added tothe housing part 1502B in an aseptic environment, and drive piston 1511is added to the housing part 1502B to seal the dispensable substance1504 in the housing part 1502B. In step 1524, the housing part 1502A andits components are assembled in a clean environment. The drive plunger1512 is used to compress the springs 1510A and 1510B, and the driveplunger 1512 is held in place via the pins 1514 and 1516. In step 1526,the resulting modules are assembled in a clean environment to producethe ingestible device 1500.

FIG. 16 shows an exemplary process flow chart 1600 for use of aningestible device in which pressure is not applied to the dispensablesubstance before the subject swallows the ingestible device. The processbeings at step 1602, when the patient swallows the ingestible device. Instep 1604, a triggering condition (e.g., pH, change in pH, presence ofcertain enzyme, concentration of certain enzyme) is met in the GI tract,thereby triggering the drive force generator. In step 1606, the driveforce mechanism applies pressure to the dispensable substance, resultingdelivery of a jet of the dispensable substance from the ingestibledevice for each opening. In step 1608, the jet has a sufficient jetstable length for the jet to impact the GI tissue of the subject. Instep 1610, the peak jet power of the jet is sufficient to achievetrans-epithelial delivery of the therapeutic agent contained in thedispensable substance. In step 1612, the fluid pressure of thedispensable substance decreases during delivery but is sufficiently sothat the peak jet power continues to be sufficient to achievetrans-epithelial delivery of the therapeutic agent contained in thedispensable substance.

FIG. 17 shows an embodiment of an ingestible device 1700 fortrans-epithelial delivery, which contains a dispensable substance thatis not under pressure when the subject swallows the ingestible device.The device 1700 has a housing 1702 with a fluid volume 1704 containing adispensable substance, nozzles 1706, nozzle openings 1708, coverings1709 over openings 1708, a spring 1710, a piston 1712, a fluid barrier1713 (to prevent the dispensable substance from contacting the piston1712 or the spring 1710), a pin 1714 and a pin 1716. When the device1700 is swallowed by the subject, the pins 1714 and 1716 prevent thedispensable substance in fluid volume 1704 from being under pressurefrom the spring 1710 and the piston 1712, and the coverings 1709 preventthe dispensable substance from exiting the device via openings 1708.When the device 1700 reaches the appropriate location in the GI tract,the pin 1714 erodes, degrades and/or dissolves (e.g., due to pH, changein pH, presence of certain enzyme, and/or concentration of certainenzyme), and the pin 1716 is no longer sufficient to hold back thepressure from the spring 1710 and the piston 1712. Thus, the pressure ofthe spring 1710 and the piston 1712 is applied to the dispensablesubstance in the fluid volume 1704, forcing the seals 1709, which aremade of a relatively low mechanical strength material (e.g., a foil or afilm) to break so that the dispensable substance is delivered out of thenozzle openings 1708 in the form of a jet. This results in intrans-epithelial delivery of the therapeutic agent contained in thedispensable substance.

FIG. 18 shows an embodiment of an ingestible device 1800 fortrans-epithelial delivery, which contains a dispensable substance thatis not under pressure when the subject swallows the ingestible device.The device 1800 has a housing 1802 with a fluid volume 1804 containing adispensable substance, nozzles 1806, nozzle openings 1808, coverings1809 over openings 1808, a spring 1810, a piston 1812, a pin 1814 and apin 1816. When the device 1800 is swallowed by the subject, the pins1814 and 1816 prevent the dispensable substance in fluid volume 1804from being under pressure from the spring 1810 and the piston 1812, andthe coverings 1809 prevent the dispensable substance from exiting thedevice via openings 1808. When the device 1800 reaches the appropriatelocation in the GI tract, the pin 1814 erodes, degrades and/or dissolves(e.g., due to pH, change in pH, presence of certain enzyme, and/orconcentration of certain enzyme), and the pin 1816 is no longersufficient to hold back the pressure from the spring 1810 and the piston1812. Thus, the pressure of the spring 1810 and the piston 1812 isapplied to the dispensable substance in the fluid volume 1804, forcingthe seals 1809, which are made of a relatively low mechanical strengthmaterial (e.g., a foil or a film) to break so that the dispensablesubstance is delivered out of the nozzle openings 1808 in the form of ajet. This results in in trans-epithelial delivery of the therapeuticagent contained in the dispensable substance.

FIG. 19A shows an embodiment of an ingestible device 1900 fortrans-epithelial delivery, which contains a dispensable substance thatis not under pressure when the subject swallows the ingestible device.FIG. 19B is an exploded view of the ingestible device 1900. Theingestible device 1900 has a cap 1901, housing parts 1902A and 1902Bwith a fluid volume 1904 containing a dispensable substance, nozzles1906, nozzle openings 1908, coverings 1909 over openings 1908, a seal1913, a spring 1910, a gas cylinder 1911, a membrane 1915 surroundingthe gas cylinder 1911, a piercer 1912, a pin 1914, a pin 1916, and anO-ring 1919. The cap 1901 is removed before the subject swallows theingestible device 1900. When the device 1900 is swallowed by thesubject, the pins 1914 and 1916 prevent the dispensable substance influid volume 1904 from being under pressure by holding the spring 1910and the piercer 1912 in place. When the device 1900 reaches theappropriate location in the GI tract, the pin 1914 erodes, degradesand/or dissolves (e.g., due to pH, change in pH, presence of certainenzyme, and/or concentration of certain enzyme), and the pin 1916 is nolonger sufficient to hold back the pressure from the spring 1910. Thespring forces the piercer 1912 into the gas cylinder 1911, puncturingthe gas cylinder 1911 and causing gas at elevated pressure to leave thecylinder 1911. This causes the cylinder to press against the membrane1915, which expands against the seal 1913. The seal 1913 is made of arelatively low mechanical strength material (e.g., a foil or a film),which breaks when pressed against by the expanding membrane 1915. Thiscauses the expanding membrane 1915 to apply pressure against thedispensable substance in the fluid volume 1904. This causes thecoverings 1909, which are made of a relatively low mechanical strengthmaterial (e.g., a foil or a film), to break so that the dispensablesubstance is delivered out of the nozzle openings 1908 in the form of ajet. This results in in trans-epithelial delivery of the therapeuticagent contained in the dispensable substance. In some embodiments, thehousing of the ingestible device 1900 is about 26 millimeters long, hasa diameter of about 11 mm, a wall thickness of about 0.8 mm Newtons, anend round of about 1.5 mm, an internal volume of about 1685 μL. In suchembodiments, the fluid volume 1904 can be about 425 μL. In someembodiments, the ingestible device 1900 does not include coverings 1909.

FIG. 19C schematically shows certain aspects of a process for theassembly of the ingestible device 1900. In step 1920, the housing part1902 is combined with the cap 1901 and coverings 1909. In step 1922, thedispensable substance 1904 is added to the housing part 1902B in anaseptic environment, and the seal 1913 is added. In step 1924, thehousing part 1902A and its components are assembled in a cleanenvironment. The piercer 1912 is held in place by pins 1914 and 1916,and the gas cylinder 1911 is held in place by components of thisassembly. In step 1926, the resulting modules are combined to providethe ingestible device 1900.

FIG. 19D shows an ingestible device 19001 for trans-epithelial delivery,which contains a dispensable substance that is not under pressure whenthe subject swallows the ingestible device. The ingestible device 19001has housing parts 1902A1 and 1902B1 with a fluid volume 19041 containinga dispensable substance, nozzles 19061, nozzle openings 19081, coverings19091 over openings 19081, a spring 19101, a gas cylinder 19111, apiston 19151, a piercer 19121, and an O-ring 19191. The pins used as thetriggering mechanism are not shown in FIG. 19D but are similarlyconfigured as pins 1914 and 1916 in FIG. 19A. When the device 19001 isswallowed by the subject, the pins prevent the dispensable substance influid volume 19041 from being under pressure by holding the spring 19101and the piercer 19121 in place. When the device 19001 reaches theappropriate location in the GI tract, one of the pins erodes, degradesand/or dissolves (e.g., due to pH, change in pH, presence of certainenzyme, and/or concentration of certain enzyme), and the other pin is nolonger sufficient to hold back the pressure from the spring 19101. Thespring forces the piercer 19121 into the gas cylinder 19111, puncturingthe gas cylinder 19111 and causing gas at elevated pressure to leave thecylinder 19111. This causes the gas cylinder 19111 to press against thepiston 19151 and apply pressure to the fluid volume 19041. This causesthe coverings 19091, which are made of a relatively low mechanicalstrength material (e.g., a foil or a film), to break so that thedispensable substance is delivered out of the nozzle openings 19081 inthe form of a jet. This results in in trans-epithelial delivery of thetherapeutic agent contained in the dispensable substance. In someembodiments, the housing of the ingestible device 19001 has a diameterof about 11 mm, a length of about 26 mm, a wall thickness of about 0.8mm, an end round of about 5.5 mm (spherical), and an internal volume ofabout 1475 μL. In such embodiments, a fluid volume 19041 can be about400 μL, and a gas volume in the gas cylinder 19111 can be about 255 μL.

FIG. 19E shows an ingestible device 19002 for trans-epithelial delivery,which contains a dispensable substance that is not under pressure whenthe subject swallows the ingestible device. The ingestible device 19002has housing parts 1902A2 and 1902B2 with a fluid volume 19042 containinga dispensable substance, nozzles 19062, nozzle openings 19082, coverings19092 over openings 19082, a spring 19102, a gas cylinder 19112, apiston 19152, a piercer 19122, and an O-ring 19192. The pins used as thetriggering mechanism are not shown in FIG. 19E but are similarlyconfigured as pins 1914 and 1916 in FIG. 19A. When the device 19002 isswallowed by the subject, the pins prevent the dispensable substance influid volume 19042 from being under pressure by holding the spring 19102and the piercer 19122 in place. When the device 19002 reaches theappropriate location in the GI tract, one of the pins erodes, degradesand/or dissolves (e.g., due to pH, change in pH, presence of certainenzyme, and/or concentration of certain enzyme), and the other pin is nolonger sufficient to hold back the pressure from the spring 19102. Thespring forces the piercer 19122 into the gas cylinder 19112, puncturingthe gas cylinder 19112 and causing gas at elevated pressure to leave thecylinder 19112. This causes the gas cylinder 19112 to press against thepiston 19152 and apply pressure to the fluid volume 19042. This causesthe coverings 19092, which are made of a relatively low mechanicalstrength material (e.g., a foil or a film), to break so that thedispensable substance is delivered out of the nozzle openings 19082 inthe form of a jet. This results in in trans-epithelial delivery of thetherapeutic agent contained in the dispensable substance. In someembodiments, the housing of the ingestible device 19002 has a diameterof about 9.9 mm, a length of about 26.1 mm, a wall thickness of about0.7 mm, a fluid volume 19042 of about 445 μL, a gas volume in the gascylinder 19112 of about 193 μL.

FIG. 19F shows an ingestible device 19003 for trans-epithelial delivery,which contains a dispensable substance that is not under pressure whenthe subject swallows the ingestible device. The ingestible device 19003has housing parts 1902A3 and 1902B3 with a fluid volume 19043 containinga dispensable substance, nozzles 19063, nozzle openings 19083, coverings19093 over openings 19083, a spring 19103, a gas cylinder 19113, a pin19143, a pin 19163, a piston 19153, a piercer 19123, and an O-ring19193. When the device 19003 is swallowed by the subject, the pins 19143and 19163 prevent the dispensable substance in fluid volume 19043 frombeing under pressure by holding the spring 191033 and the piercer 19123in place. When the device 19003 reaches the appropriate location in theGI tract, the pin 19143 erodes, degrades and/or dissolves (e.g., due topH, change in pH, presence of certain enzyme, and/or concentration ofcertain enzyme), and the pin 19163 is no longer sufficient to hold backthe pressure from the spring 19103. The spring forces the piercer 19123into the gas cylinder 19113, puncturing the gas cylinder 19113 andcausing gas at elevated pressure to leave the cylinder 19113. Thiscauses the gas cylinder 19113 to press against the piston 19153 andapply pressure to the fluid volume 19043. This causes the coverings19093, which are made of a relatively low mechanical strength material(e.g., a foil or a film), to break so that the dispensable substance isdelivered out of the nozzle openings 19083 in the form of a jet. Thisresults in in trans-epithelial delivery of the therapeutic agentcontained in the dispensable substance. In some embodiments, the housingof the ingestible device 19003 has a diameter of about 8.5 mm, a lengthof about 23.3 mm, a wall thickness of about 0.7 mm, an end round ofabout 4.25 mm (spherical), and an internal volume of about 775 μL. Insuch embodiments, the fluid volume 19043 can be about 205 μL, and a gasvolume in the gas cylinder 19113 can be about 160 μL.

FIG. 19G shows an ingestible device 19004 for trans-epithelial delivery,which contains a dispensable substance that is not under pressure whenthe subject swallows the ingestible device. The ingestible device 19004has housing parts 1902A4 and 1902B4 with a fluid volume 19044 containinga dispensable substance, nozzles 19064, nozzle openings 19084, coverings19094 over openings 19084, a spring 19104, a gas cylinder 19114, a pin19144, a pin 19164, a gas cylinder 19114, a seal 19134, a membrane19154, a piercer 19124, a pin 19144, and a pin 19164, and an O-ring19194. When the device 19004 is swallowed by the subject, the pins 19144and 19164 prevent the dispensable substance in fluid volume 19044 frombeing under pressure by holding the spring 19104 and the piercer 19124in place. When the device 19004 reaches the appropriate location in theGI tract, the pin 19144 erodes, degrades and/or dissolves (e.g., due topH, change in pH, presence of certain enzyme, and/or concentration ofcertain enzyme), and the pin 19164 is no longer sufficient to hold backthe pressure from the spring 19104. The spring forces the piercer 19124into the gas cylinder 19114, puncturing the gas cylinder 19114 andcausing gas at elevated pressure to leave the cylinder 19114. Thiscauses the cylinder to press against the membrane 19154, which expandsagainst the seal 19134. The seal 19134 is made of a relatively lowmechanical strength material (e.g., a foil or a film), which breaks whenpressed against by the expanding membrane 19154. This causes theexpanding membrane 19154 to apply pressure against the dispensablesubstance in the fluid volume 19044. This causes the coverings 19094,which are made of a relatively low mechanical strength material (e.g., afoil or a film), to break so that the dispensable substance is deliveredout of the nozzle openings 19084 in the form of a jet. This results inin trans-epithelial delivery of the therapeutic agent contained in thedispensable substance. In some embodiments, the housing of theingestible device 19004 is about 26 millimeters long, has a diameter ofabout 11 mm, and a wall thickness of about 0.8 mm Newtons. In suchembodiments, the fluid volume 19044 can be about 410 μL. In suchembodiments, the gas volume of the gas cylinder 19114 can be about 216μL, and the spring 19104 can provide a force of about 80 Newtons.

FIG. 19H shows an ingestible device 19005 for trans-epithelial delivery,which contains a dispensable substance that is not under pressure whenthe subject swallows the ingestible device. The ingestible device 19005has housing parts 1902A5 and 1902B5 with a fluid volume 19045 containinga dispensable substance, nozzles 19065, nozzle openings 19085, coverings19095 over openings 19085, a spring 19105, a gas cylinder 19115, a pin19145, a pin 19165, a gas cylinder 19115, a membrane 19155, a piercer19125, a pin 19145, and a pin 19165, and O-rings 19195. When the device19005 is swallowed by the subject, the pins 19145 and 19165 prevent thedispensable substance in fluid volume 19045 from being under pressure byholding the spring 19105 and the piercer 19125 in place. When the device19005 reaches the appropriate location in the GI tract, the pin 19145erodes, degrades and/or dissolves (e.g., due to pH, change in pH,presence of certain enzyme, and/or concentration of certain enzyme), andthe pin 19165 is no longer sufficient to hold back the pressure from thespring 19105. The spring forces the piercer 19125 into the gas cylinder19115, puncturing the gas cylinder 19115 and causing gas at elevatedpressure to leave the cylinder 19115. This causes the cylinder to pressagainst the membrane 19155, which causes the expanding membrane 19155 toapply pressure against the dispensable substance in the fluid volume19045. This causes the coverings 19095, which are made of a relativelylow mechanical strength material (e.g., a foil or a film), to break sothat the dispensable substance is delivered out of the nozzle openings19085 in the form of a jet. This results in in trans-epithelial deliveryof the therapeutic agent contained in the dispensable substance. In someembodiments, the housing of the ingestible device 19005 is about 23.3millimeters long, has a diameter of about 8.5 mm, and a wall thicknessof about 0.7 mm. In such embodiments, the fluid volume 19045 can beabout 300 μL. In such embodiments, the gas volume of the gas cylinder19115 can be about 247 μL.

FIG. 19I shows a portion of an ingestible device including a housingpart 19028, a gas cylinder 19118 with a membrane 19018, a piercer 19128that is held in place via an enteric material 19148, and a biaseddiaphragm 19039. FIG. 19J shows corresponding portions of the ingestibledevice after the enteric material 19148 degrades/dissolves/erodes. Thediaphragm 19038 has moved so that the piercer 19126 has pierced themembrane 19016, causing the gas in the gas cylinder 19116 to escape.Although not shown, the gas pressure causes another housing part (e.g.,the housing part of the drug module) to move, to expose nozzle openingsso that the dispensable substance leaves the ingestible device in theform jets for trans-epithelial delivery.

FIG. 19K shows a portion of an ingestible device including a housingpart 19026, a gas cylinder 19116 with a membrane 19016, a piercer 19126that is held in place via an enteric material 19146, stabilizingelements 19036A and 19036B, and a biasing element 19038 (e.g., a discspring). FIG. 19K shows corresponding portions of the ingestible deviceafter the enteric material 19146 degrades/dissolves/erodes. The springbiasing element 19038 has moved so that the piercer 19126 has piercedthe membrane 19016, causing the gas in the gas cylinder 19116 to escape.Although not shown, the gas pressure causes another housing part (e.g.,the housing part of the drug module) to move, to expose nozzle openingsso that the dispensable substance leaves the ingestible device in theform jets for trans-epithelial delivery.

FIG. 20A shows an embodiment of an ingestible device 2000 fortrans-epithelial delivery, containing a dispensable substance that isnot under pressure when the subject swallows the ingestible device. Thedevice 2000 has housing parts 2002A and 2002B with a fluid volume 2004containing a dispensable substance, nozzles 2006, nozzle openings 2008,seals 2009 over openings 2008, a seal 2013, a gas cylinder 2011, amembrane 2015 between the seal 2013 and the gas cylinder 2011, a biasedpiercer 2012, and a plug 2013. When the device 2000 is swallowed by thesubject, the plug 2013 keeps the piercer in its biased position as shownin FIG. 20A. When the device 2000 reaches the appropriate location inthe GI tract, the plug 2013 erodes, degrades and/or dissolves (e.g., dueto pH, change in pH, presence of certain enzyme, and/or concentration ofcertain enzyme), and the piercer 2012 moves axially to pierce the gascylinder 2011 and cause gas at elevated pressure to leave the cylinder2011. This causes the cylinder to press against the membrane 2015, whichbreaks the seal 2013 so that the pressure is applied against thedispensable substance in the fluid volume 2004. This causes thecoverings 2009, which are made of a relatively low mechanical strengthmaterial (e.g., a foil or a film), to break so that the dispensablesubstance is delivered out of the nozzle openings 2008 in the form of ajet. This results in trans-epithelial delivery of the therapeutic agentcontained in the dispensable substance.

FIG. 20B schematically shows certain aspects of the assembly of theingestible device 2000. The housing parts 2002A (including the seal2013) and 2002B (including the membrane 2015, the gas cylinder 2011 andthe piercer 2012) are initially separate from each other. Thedispensable substance (including the therapeutic agent) is firststerilized, and then disposed in the fluid volume 2004 under asepticconditions. The components in housing part 2002B are assembled in aclean environment. Subsequently, the housing parts 2002A and 2002B arejoined in a clean environment to produce the ingestible device 2000.

FIG. 21A shows an embodiment of an ingestible device 2100 fortrans-epithelial delivery, containing a dispensable substance that isnot under pressure when the subject swallows the ingestible device. Thedevice 2100 has housing parts 2102A and 2102B with a fluid volume 2104containing a dispensable substance, nozzles 2106, nozzle openings 2108,a bellows 2110, a gas cylinder 2111, a biased piercer 2112, and a plug2113. When the device 2100 is swallowed by the subject, the plug 2113keeps the piercer in its biased position as shown in FIG. 20A. When thedevice 2100 reaches the appropriate location in the GI tract, the plug2113 erodes, degrades and/or dissolves (e.g., due to pH, change in pH,presence of certain enzyme, and/or concentration of certain enzyme), andthe piercer 2112 moves axially to pierce the gas cylinder 2111 and causegas at elevated pressure to leave the cylinder 2111. This gas pressureis applied against press against the bellows 2110, causing the bellows2110 such that holes in the bellows 21120 (not shown) align with thenozzles 2106 so that the dispensable substance is delivered out of thenozzle openings 2008 in the form of a jet. This results intrans-epithelial delivery of the therapeutic agent contained in thedispensable substance.

FIG. 21B schematically shows certain aspects of the assembly of theingestible device 2100. The housing parts 2102A (including the bellows2110) and 2102B (including the gas cylinder 2111 and the piercer 2112)are initially separate from each other. The dispensable substance(including the therapeutic agent) is first sterilized, and then disposedin the fluid volume 2104 under aseptic conditions. The components inhousing part 2102B are assembled in a clean environment. Subsequently,the housing parts 2102A and 2102B are joined in a clean environment toproduce the ingestible device 2100.

Device for Epithelial Delivery

Generally, epithelial delivery can be achieved at any desired locationwithin the GI tract of a subject. In some embodiments, epithelialdelivery is achieved in the small intestine of the subject, such as, forexample, in the duodenum, the jejunum and/or the ileum. In certainembodiments, epithelial delivery is achieved in the large intestine ofthe subject, such as, for example, the cecum or the colon.

In some embodiments, epithelial delivery can be achieved using any oneof the ingestible devices described above with respect to epithelialdelivery. In such embodiments, the relevant parameters are usuallymodified accordingly. Typically, this modification involves modifyingthe values for the relevant parameters. Examples are provided in thefollowing paragraphs.

In general, an ingestible device for epithelial delivery is configuredto deliver a jet of the dispensable substance having a peak jet power ofat least about 1 mW (e.g., at least about 1.5 mW, at least about 2 mW,at least about 2.5 mW) and/or at most about 4 mW (e.g., at most about3.5 mW, at most about 3 mW). In some embodiments, an ingestible devicefor epithelial delivery is configured to deliver a jet of thedispensable substance having a peak jet power of from about 1 mW toabout 4 mW (e.g., from about 1 mW to about 3.5 mW, from about 2 mW toabout 3 mW).

Generally, an ingestible device for epithelial delivery is configured todeliver a jet of the dispensable substance having a peak jet pressure ofabout 2 psig (e.g., about 2.5 psig, about 3 psig, about 3.5 psig, about4 psig) and/or at most about 10 psig (e.g., at most about 8 psig, atmost about 6 psig, at most about 5 psig). In some embodiments, aningestible device for epithelial delivery is configured to deliver a jetof the dispensable substance having a peak jet pressure of from about 2psig to about 10 psig (e.g., from about 2.5 psig to about 8 psig, fromabout 3 psig to about 6 psig, from about 3.5 psig to about 5 psig, fromabout 4 psig to about 5 psig).

In general, an ingestible device for epithelial delivery is configuredto deliver a jet of the dispensable substance having a peak jet force ofat least about 0.5 mN (e.g., at least about 0.6 mN, at least about 0.7mN, at least about 0.8 mN, at least about 0.9 mN) and/or at most about 2mN (e.g., at most about 1.8 mN, at most about 1.6 mN, at most about 1.4mN, at most about 1.2 mN). In some embodiments, an ingestible device forepithelial delivery is configured to deliver a jet of the dispensablesubstance having a peak jet force of from about 0.5 mN to about 2 mN(e.g., from about 0.6 mN to about 1.8 mN, from about 0.7 mN to about 1.6mN, from about 0.8 mN to about 1.4 mN, from about 0.9 mN to about 1.2mN).

In general, an ingestible device for epithelial delivery is configuredto deliver a jet of the dispensable substance having a minimum jetvelocity of from at least about 2 m/s (e.g., at least about 3 m/s, atleast about 4 m/s, at least about 5 m/s) and/or at most about 20 m/s(e.g., at most about 15 m/s, at most about 10 m/s, at most about 8 m/s).In some embodiments, an ingestible device for epithelial delivery isconfigured to deliver a jet of the dispensable substance having a peakjet velocity of from about 2 m/s to about 20 m/s (e.g., from about 3 m/sto about 15 m/s, from about 4 m/s to about 10 m/s, from about 5 m/s toabout 8 m/s).

In general, an ingestible device for epithelial delivery is configuredto provide an internal pressure of from about 3.62 psig to about 21.76psig (e.g., from about 3.62 psig to about 18.13 psig, from about 3.62psig to about 14.50 psig, from about 3.62 psig to about 10.88 psig, fromabout 3.62 psig to about 7.25 psig, from about 4.35 psig to about 7.25psig, about 4.35 psig).

In general, an ingestible device for epithelial delivery is configuredto provide a nozzle pressure of from about 3.62 psig to about 21.76 psig(e.g., from about 3.62 psig to about 18.13 psig, from about 3.62 psig toabout 14.50 psig, from about 3.62 psig to about 10.88 psig, from about3.62 psig to about 7.25 psig, from about 4.35 psig to about 7.25 psig,about 4.35 psig).

Generally, an ingestible device for epithelial delivery is configured tocontain a dispensable substance at a peak fluid pressure from 3.62 psigto about 21.76 psig (e.g., from about 3.62 psig to about 18.13 psig,from about 3.62 psig to about 14.50 psig, from about 3.62 psig to about10.88 psig, from about 3.62 psig to about 7.25 psig, from about 4.35psig to about 7.25 psig, about 4.35 psig).

In general, an ingestible device for epithelial delivery contains thedispensable substance at an initial fluid volume of at least about 50microliters (μL) (e.g., at least about 100 μL, at least about 150 μL, atleast about 200 μL, at least about 250 μL) and/or at most about 800 μL,(e.g., at most about 700 μL, at most about 600 μL, at most about 500 μL,at most about 400 μL). In some embodiments, an ingestible device forepithelial delivery contains the dispensable substance at an initialfluid volume of from about 50 μL to about 800 μL (e.g., from about 100μL to about 600 μL, from about 200 μL to about 400 μL).

Generally, an ingestible device for epithelial delivery is configured toprovide a delivered fluid volume of dispensable substance of at leastabout 50 microliters (μL) (e.g., at least about 100 μL, at least about150 μL, at least about 200 μL, at least about 250 μL) and/or at mostabout 800 μL (e.g., at most about 700 μL, at most about 600 μL, at mostabout 500 μL, at most about 400 μL). In some embodiments, an ingestibledevice for epithelial delivery has a fluid volume of dispensablesubstance of from about 50 μL to about 800 μL (e.g., from about 100 μLto about 600 μL, from about 200 μL to about 400 μL).

In general, an ingestible device for epithelial delivery contains thedispensable substance at a final fluid volume of at most about 100microliters (μL) (e.g., at least about 90 μL, at least about 80 μL, atleast about 70 μL, at least about 60 μL) and/or at most least 5 μL(e.g., at most about 10 μL, at most about 20 μL, at most about 30 μL, atmost about 40 μL). In some embodiments, an ingestible device forepithelial delivery contains the dispensable substance at a fluid volumeof from about 30 μL to about 70 μL (e.g., from about 40 μL to about 60μL, from about 45 μL to about 55 μL).

In general, an ingestible device for epithelial delivery is configuredto directly deliver at least about 50% (e.g., at least about 60%, atleast about 70%, at least about 80%, at least about 90%, at least about95%, at least about 97%) of the dispensable substance from theingestible device to the mucus.

In general, an ingestible device for epithelial delivery is configuredto provide a delivered fluid volume per opening for delivery ofdispensable substance (e.g., per nozzle) of at least about 20microliters (μL) (e.g., at least about 25 μL, at least about μL, atleast about 50 μL, at least about 75 μL, at least about 100 μL) and/orat most about 800 μL (e.g., at most about 700 μL, at most about 600 μL,at most about 500 μL, at most about 400 μL, at most about 300 μL). Insome embodiments, an ingestible device for epithelial delivery isconfigured to provide a delivered fluid volume per opening for deliveryof dispensable substance (e.g., per nozzle) of from about 25 μL to about400 μL (e.g., from about 25 μL to about 300 μL, from about 100 μL toabout 300 μL).

In certain embodiments, an ingestible device for epithelial delivery isconfigured as disclosed in the above-discussion regardingtrans-epithelial delivery, but with a relatively large number of nozzlesand a relatively large nozzle diameter such that performance propertiesfor epithelial delivery (discussed above) can be achieved. As anexample, in some embodiments, an ingestible device for epithelialdelivery has at least 25 nozzles (e.g., at least 30 nozzles, at least 40nozzles, 50 nozzles). In some embodiments, such an ingestible device forepithelial delivery has 30 nozzles, 31 nozzles, 32 nozzles, 33 nozzles,34 nozzles, 35 nozzles, 36 nozzles, 37 nozzles, 38 nozzles or 40nozzles. Each nozzle can have a diameter, for example, of at least about1 mm (e.g., at least about 1.5 mm, at least about 2 mm) and/or at mostabout 3 mm (e.g., at most about 2.5 mm). For example, in such aningestible device, each nozzle can have a diameter of from about 1 mm toabout 3 mm (e.g., from about 1 mm to about 2.5 mm, from about 2 to 2.5mm).

Device for Topical Delivery

Generally, topical delivery can be achieved at any desired locationwithin the GI tract of a subject. In some embodiments, topical deliveryis achieved in the small intestine of the subject, such as, for example,in the duodenum, the jejunum and/or the ileum. In certain embodiments,topical delivery is achieved in the large intestine of the subject, suchas, for example, the cecum or the colon.

In general, an ingestible device for topical delivery is configured toprovide an internal pressure of at least about 5 psig (e.g., at leastabout 8 psig, at least about 10 psig) and/or at most about 50 psig(e.g., at most about 40 psig, at most about 30 psig, at most about 20psig, at most about 15 psig). In certain embodiments, an ingestibledevice for topical delivery is configured to provide an internalpressure of from about 5 psig to about 50 psig (e.g., from about 5 psigto about 30 psig, from about 5 psig to about 20 psig, from about 8 psigto about 20 psig, from about 10 psig to about 15 psig).

Generally, an ingestible device for topical delivery is configured tocontain a dispensable substance at a peak fluid pressure of at leastabout 5 psig (e.g., at least about 8 psig, at least about 10 psig)and/or at most about 50 psig (e.g., at most about 40 psig, at most about30 psig, at most about 20 psig, at most about 15 psig). In certainembodiments, an ingestible device for topical delivery is configured todeliver a jet of the dispensable substance having a peak fluid pressureof from about 5 psig to about 50 psig (e.g., from about 5 psig to about30 psig, from about 5 psig to about 20 psig, from about 8 psig to about20 psig, from about 10 psig to about 15 psig).

In general, an ingestible device for topical delivery is configured todeliver at least about 50% (e.g., at least about 60%, at least about70%, at least about 80%, at least about 90%, at least about 95%, atleast about 97%) of the dispensable substance from the ingestible deviceinto the lumen of the GI tract.

In general, an ingestible device for topical delivery contains thedispensable substance at an initial fluid volume of at least about 50microliters (μL) (e.g., at least about 100 μL, at least about 150 μL, atleast about 200 μL, at least about 250 μL) and/or at most about 800 μL(e.g., at most about 700 μL, at most about 600 μL, at most about 500 μL,at most about 400 μL). In some embodiments, an ingestible device fortopical delivery contains the dispensable substance at an initial fluidvolume of from about 50 μL to about 800 μL (e.g., from about 100 μL toabout 600 μL, from about 200 μL to about 400 μL).

In general, an ingestible device for topical delivery contains thedispensable substance at a final fluid volume of at most about 100microliters (μL) (e.g., at least about 90 μL, at least about 80 μL, atleast about 70 μL, at least about 60 μL) and/or at most least 5 μL(e.g., at most about 10 μL, at most about 20 μL, at most about 30 μL, atmost about 40 μL). In some embodiments, an ingestible device for topicaldelivery contains the dispensable substance at a fluid volume of fromabout 30 μL to about 70 μL (e.g., from about 40 μL to about 60 μL, fromabout 45 μL to about 55 μL).

FIG. 23A shows an embodiment of an ingestible device 2300 for topicaldelivery. FIG. 23B is an exploded view of the ingestible device 2300.The ingestible device 2300 has housing parts 2302A and 2302B, a fluidvolume 2304 containing a dispensable substance, an O-ring 2305, and aband 2306. The device 2300 has a head space pressure in the housing part2302B, but the band 2306 holds the components of device 2300 in placewhen the device 2300 is swallowed by the subject. When the device 2300reaches the appropriate location in the GI tract, the band 2306 erodes,degrades and/or dissolves, and the head space pressure causes thehousing part 2302B to leave device 2300, resulting in the therapeuticagent in the dispensable substance being topically delivered to the GItract of the subject. In embodiments having a design substantiallysimilar to the ingestible device 2300, the head space pressure isprovided by a gas, such as, for example, air nitrogen (N₂), oxygen (O₂),an inert gas (e.g., argon (Ar), krypton (Kr), helium (He)), and/orcarbon dioxide (CO₂). In embodiments having a design substantiallysimilar to the ingestible device 2300, the head space pressure cancorrespond to the internal pressure of the ingestible device. Inembodiments having a design substantially similar to the ingestibledevice 2300, the head space pressure can correspond to the fluidpressure of the ingestible device.

FIG. 24 shows an embodiment of an ingestible device 2400 for topicaldelivery. The ingestible device 2400 has housing parts 2402A and 2402B,a fluid volume 2404 containing a dispensable substance, an O-ring 2405,and pins 2406 and 2408. The device 2400 has a head space pressure in thehousing part 2402B, but the pins 2406 and 2408 hold the components ofdevice 2400 in place when the device 2400 is swallowed by the subject.When the device 2400 reaches the appropriate location in the GI tract,the pins 2406 and 2408 erode, degrade and/or dissolve, and the headspace pressure causes the housing part 2402B to leave device 2400,resulting in the therapeutic agent in the dispensable substance beingtopically delivered to the GI tract of the subject. In embodimentshaving a design substantially similar to the ingestible device 2400, thehead space pressure is provided by a gas, such as, for example, airnitrogen (N₂), oxygen (O₂), an inert gas (e.g., argon (Ar), krypton(Kr), helium (He)), and/or carbon dioxide (CO2). In embodiments having adesign substantially similar to the ingestible device 2400, the headspace pressure can correspond to the internal pressure of the ingestibledevice. In embodiments having a design substantially similar to theingestible device 2400, the head space pressure can correspond to thefluid pressure of the ingestible device.

FIG. 25 shows an embodiment of an ingestible device 2500 for topicaldelivery. The ingestible device 2500 has housing parts 2502A and 2502B,a fluid volume 2504 containing a dispensable substance, and a partialcoating 2506. The device 2500 has a head space pressure within thehousing part 2502A, but the partial coating 2506 holds the components ofdevice 2500 in place when the device 2500 is swallowed by the subject.When the device 2500 reaches the appropriate location in the GI tract,the partial coating 2506 erodes, degrades and/or dissolves, and the headspace pressure causes the housing parts 2502A and 2502B to separate fromeach other, resulting in the therapeutic agent in the dispensablesubstance being topically delivered to the GI tract of the subject. Inembodiments having a design substantially similar to the ingestibledevice 2500, the head space pressure is provided by a gas, such as, forexample, air nitrogen (N₂), oxygen (O₂), an inert gas (e.g., argon (Ar),krypton (Kr), helium (He)), and/or carbon dioxide (CO₂). In embodimentshaving a design substantially similar to the ingestible device 2500, thehead space pressure can correspond to the internal pressure of theingestible device. In embodiments having a design substantially similarto the ingestible device 2500, the head space pressure can correspond tothe fluid pressure of the ingestible device.

FIG. 26A shows an ingestible device 2600 that can be used for topicaldelivery. FIG. 26B is an exploded view of the device 2600. The device2600 includes a first housing part 2602A, a second housing part 2602Band a third housing part 2602C. The device 2600 further includes a fluidvolume 2604 containing a dispensable substance, a spring 2606, a plunger2608, a piston 2610, an O-ring 2609, and a stopper pin 2612 which holdsthe components of the device 2600 when the subject swallows the device2600. When the device 2600 reaches the appropriate location in the GItract, the pin 2612 erodes, degrades and/or dissolves. Thus, thepressure of the spring 2606 is applied to the plunger 2608, which movesthe piston 2610 axially. This pressure is transferred to the dispensablesubstance in the fluid volume 2604, which forces the housing part 2602Cto be removed from the device 2600, and the therapeutic agent in thedispensable substance is topically delivered.

FIG. 26C shows aspects of steps in assembling the ingestible device2600. In step 2620, the housing parts 2602B and 2602C are combined andthen sterilized. In step 2622, the dispensable substance 2604 isdisposed in the housing parts 2602B and 2602C in an aseptic environmentand then sealed within the piston 2610. In step 2624, the housing part2602A and its components are assembled in a clean environment. In step2626, the resulting modules are joined together in a clean environmentto provide the ingestible device 2600.

FIG. 27 shows an ingestible device 2700 that can be used for topicaldelivery. The device 2700 includes a first housing part 2702A and asecond housing part 2702B. The device 2700 further includes a fluidvolume 2704 containing a dispensable substance, a spring 2706, a seal2708 (e.g., a foil or a film) and a partial coating 2710 which holds thecomponents of the device 2700 when the subject swallows the device 2700.When the device 2700 reaches the appropriate location in the GI tract,the partial coating 2710 erodes, degrades and/or dissolves. The spring2706 then exerts a pressure axially against the dispensable substance2704, breaking the seal 2708 and also causing the housing parts 2702Aand 2702B to separate, which results in topical delivery of thetherapeutic agent in the dispensable substance.

FIG. 28A shows an ingestible device 2800 that can be used for topicaldelivery. The device 2800 includes a first housing part 2802A and asecond housing part 2802B. The device 2800 further includes a fluidvolume 2804 containing a dispensable substance, a spring 2806, a seal2808, an O-ring 2809, and a partial coating 2810 which holds thecomponents of the device 2800 when the subject swallows the device 2800.When the device 2800 reaches the appropriate location in the GI tract,the partial coating 2810 erodes, degrades and/or dissolves. As shown inFIG. 28B, this causes the spring 2806 to expand so that housing parts2802A and 2802B separate, resulting in topical delivery of thetherapeutic agent in the dispensable substance.

FIG. 29A shows an ingestible device 2900 for topical delivery. FIG. 29Bis an exploded view of the device 2900. The device 2900 includes housingparts 2902A, 2902B and 2902C. The device also includes a fluid volume2904 containing a dispensable substance, an O-ring 2906, a piston 2908 agas cell 2910 (e.g., a hydrogen cell), a potting material 2911, anelectrical contact 2912, and a plug 2914. The subject swallows thedevice 2900, and, when the device 2900 reaches an appropriate locationin the GI tract of the subject, the plug 2914 erodes, degrades and/ordissolves. This causes the electrical contact 2912 to energize the gascell 2910, which produces a pressurized gas (e.g., pressurized hydrogen)that pushes the piston 2908 axially. This movement applies a pressure tothe fluid volume 2904, which transfers the pressure to the housing part2902C. This causes the housing part 2902C to separate from the device2900 so that the therapeutic agent in the dispensable substance istopically delivered.

FIG. 29C shows aspects of steps in assembling the ingestible device2900. In step 2920, the housing parts 2902B and 2902C are combined andthen sterilized. In step 2922, the dispensable substance 2904 isdisposed in the housing parts 2902B and 2902C in an aseptic environmentand then sealed within the piston 2908. In step 2924, the housing part2902A and its components are assembled in a clean environment. In step2926, the resulting modules are joined together in a clean environmentto provide the ingestible device 2900.

FIG. 30 shows an ingestible device 3000 that can be used for topicaldelivery. The device 3000 includes housing parts 3002A, 3002B and 3002C.The device 2800 further includes a fluid volume 3004 containing adispensable substance, a spring 3006, a plunger 3008 with piercingelements 3009, an O-Ring 3011, a sealed compartment 3010 containingseparated reactants A and B, a piston 3010, and O-ring 3013, and astopper pin 3012 which holds the components of the device 3000 when thesubject swallows the device 3000. When the device 3000 reaches theappropriate location in the GI tract, the pin 3012 erodes, degradesand/or dissolves. This causes the spring 3006 to expand axially, movingthe plunger 3008 axially so that the piercing elements 3009 puncture thesealed compartment 3010. This causes the reactants A and B to chemicallyreact and form a pressurized gas which moves the piston axially, therebyapplying a pressure against the fluid volume 3004. This pressure istransferred to the housing part 3002C, which forces the housing part3002C to be removed from the device 3000, and the therapeutic agent inthe dispensable substance is topically delivered.

FIG. 31A shows an ingestible device 3100 for topical delivery. Thedevice 3100 includes housing parts 3102A and 3102B, a joint 3103, apressurized fluid volume 3104 containing a dispensable substance, amembrane 3106 (e.g., balloon) containing the dispensable substance, aseal 3108 located in an opening 3103 of the housing part 3102B, and aplug 3110 in an opening 3112 of the housing part 3102A. The subjectswallows the ingestible device 3100. When the device 3100 reaches theappropriate location in the GI tract, the plug 3110 erodes, degradesand/or dissolves. This causes the pressurized fluid 3104 in the membrane3104 to leave the device 3100 via the opening 3112 so that thetherapeutic agent in the dispensable substance is topically delivered.

FIG. 31B shows aspects of steps in assembling the ingestible device3100. In step 3120, the plug 3112 is formed in the opening 3112 of thehousing part 3102A, the membrane 3104 is put inside the housing part3102A, and the dispensable substance is disposed in the membrane 3104under aseptic conditions. In step 3122, the housing part 3102B iscombined with the housing part 3102A, and the open portion of themembrane 3104 is sealed (e.g., hot sealed) within the opening 3103,thereby forming the ingestible device 3100.

FIG. 32 shows an ingestible device 3200 for topical delivery. The device3200 includes housing parts 3202A and 3202B. The housing part 3202Bincludes a seal 3203. The housing part 3202A is made from a flexiblematerial that is biased against the housing part 3202B and joined to thehousing part 3202B by a partial coating 3206 such that housing. Thedevice 3200 also includes a fluid volume 3204 containing a dispensablesubstance. The subject swallows the ingestible device 3200. When thedevice 3200 reaches the appropriate location in the GI tract, thepartial coating 3206 erodes, degrades and/or dissolves. This causes theflexible housing part 3202A to expand radially so that the housing parts3202A and 3202B are separated, resulting in topical delivery of thetherapeutic agent in the dispensable substance.

FIG. 32B shows aspects of steps in assembling the ingestible device3200. In step 3220, the housing plug 3212 is formed in the opening 3212of the housing part 3202A, the membrane 3204 is put inside the housingpart 3202A, and the dispensable substance is disposed in the membrane3204 under aseptic conditions. In step 3222, the housing part 3202B iscombined with the housing part 3202A, and the open portion of themembrane 3204 is sealed (e.g., hot sealed) within an opening 3203 in thehousing part 3202B, thereby forming the ingestible device 3200.

In certain embodiments, an ingestible device for topical delivery isconfigured as disclosed in the above-discussion regardingtrans-epithelial delivery, but with a relatively large number of nozzlesand a relatively large nozzle diameter such that performance propertiesfor topical delivery (discussed above) can be achieved. As an example,in some embodiments, an ingestible device for topical delivery has atleast 25 nozzles (e.g., at least 30 nozzles, at least 40 nozzles, 50nozzles). In some embodiments, such an ingestible device for topicaldelivery has 30 nozzles, 31 nozzles, 32 nozzles, 33 nozzles, 34 nozzles,35 nozzles, 36 nozzles, 37 nozzles, 38 nozzles or 40 nozzles. Eachnozzle can have a diameter, for example, of at least about 1 mm (e.g.,at least about 1.5 mm, at least about 2 mm) and/or at most about 3 mm(e.g., at most about 2.5 mm). For example, in such an ingestible device,each nozzle can have a diameter of from about 1 mm to about 3 mm (e.g.,from about 1 mm to about 2.5 mm, from about 2 to 2.5 mm).

Delivery of Therapeutics

Provided herein are ingestible devices and methods that delivertherapeutic agents into the intestinal lumen, mucus, mucosa and/orsubmucosa by topical, epithelial or trans-epithelial administration tothe GI tract of a subject. Current methods of administration for mostlarge molecule therapeutic agents or small molecule therapeutic agentswith poor oral bioavailability are subcutaneous (SC), intramuscular(IM), or bolus intravenous (IV) injection targeting the systemiccirculation. The devices and methods described herein provide analternative route of administration to current injectable medications,which can lead to greater convenience and compliance since they minimizeor avoid the logistical challenges, patient compliance and adherencechallenges, pain, and discomfort associated with traditional routes ofadministration.

In some embodiments of the devices or methods described herein, thetherapeutic is released at a location in the small intestine of thesubject. In some embodiments of any of the devices or methods describedherein, the location is in the proximal portion of the small intestine(e.g., duodenum or jejunum). In some embodiments of any of the devicesor methods described herein, the location is in the distal portion ofthe small intestine (e.g., jejunum or ileum). In some embodiments of thedevices or methods described herein, the therapeutic is released at alocation in the large intestine of the subject. In some embodiments ofany of the devices or methods described herein, the location is in theproximal portion of the large intestine (e.g., cecum, ascending colon,or transverse colon). In some embodiments of any of the devices ormethods described herein, the location is in the distal portion of thelarge intestine (e.g., transverse colon or descending colon).

Also, by providing a higher concentration of therapeutic in GI tissue,the devices and methods described herein are particularly well-suitedfor treatment of diseases and conditions of the endoderm, including theliver.

In some embodiments of any of the devices or methods described herein,the releasing of the therapeutic is triggered by one or more of: a pH inthe jejunum of about 6.1 to about 7.2, a pH in the mid small bowel ofabout 7.0 to about 7.8, a pH in the ileum of about 7.0 to about 8.0, apH in the right colon of about 5.7 to about 7.0, a pH in the mid colonof about 5.7 to about 7.4, or a pH in the left colon of about 6.3 toabout 7.7, such as about 7.0.

In some embodiments of any of the devices or methods described herein,the releasing of the therapeutic is triggered by degradation of arelease component located in the device. In some embodiments of any ofthe devices or methods described herein, the releasing of thetherapeutic is dependent on enzymatic activity at or in the vicinity ofthe location. In some embodiments of any of the devices or methodsdescribed herein, the composition includes a plurality of electrodesincluding a coating, and releasing the therapeutic is triggered by anelectric signal by the electrodes resulting from the interaction of thecoating with an intended site of release of the therapeutic. In someembodiments of any of the devices or methods described herein, therelease of the therapeutic is triggered by a remote electromagneticsignal. In some embodiments of any of the devices or methods describedherein, the release of the therapeutic is triggered by generation in thecomposition of a gas in an amount sufficient to expel the therapeutic.In some embodiments of any of the devices or methods described herein,the release of the therapeutic is triggered by an electromagnetic signalgenerated within the device according to a pre-determined drug releaseprofile.

Therapeutics for Delivery

Therapeutics suitable for use with the devices and methods describedherein include both small molecules and large molecules. In someembodiments, the therapeutic agent is a large molecule. Examples oflarge molecules include, but are not limited to, biologic drugs,proteins including fusion proteins, peptides including cyclic peptides,cells including stem cells, and nucleic acids such as inhibitory nucleicacids, antisense nucleic acids, siRNA, ribozymes, and the like. In someembodiments, the therapeutic agent is a large molecule with a molecularweight of at least about 60 kilodaltons (kDa), or about 60 kDa to about200 kDa, about 60 kDa to about 175 kDa, or about 60 kDa to about 150kDa. In some other embodiments, the therapeutic agent has a molecularweight of at least about 20 kDa, at least about 30 kDa, at least about40 kDa, or at least about 50 kDa, or from about 20 kDa to about 200 kDa,about 20 kDa to about 175 kDa or about 20 kDa to about 150 kDa.

In some embodiments, the therapeutic agent is a molecule with amolecular weight of greater than about 1.5 kDa and less than about 20kDa, less than about 30 kDa, less than about 40 kDa, less than about 50kDa or less than about 60 kDa. In some other embodiments, thetherapeutic agent has a molecular weight of from about 5 kDa to about 10kDa, 20 kDa, 30 kDa, 40 kDa or 50 kDa. In some embodiments, thetherapeutic agent is a molecule with a molecular weight of about 5 kDato about 10 kDa, such as about 6 kDa. In some embodiments, thetherapeutic agent is a protein or peptide. In some embodiments, thetherapeutic agent is insulin.

In some embodiments, the therapeutic agent is a small molecule. A “smallmolecule,” as used herein, is a compound, typically an organic compound,having a molecular weight of about 50 Da to about 1500 Da, about 60 Dato about 1500 Da, about 500 Da to about 1000 Da, or no more than about1500 Da, about 1000 Da, about 750 Da, or about 500 Da. In someembodiments, the therapeutic agent is a small molecule with a molecularweight of about 50 Da to about 1500 Da. In some embodiments, thetherapeutic agent is a small molecule with a molecular weight of about150 Da to about 1500 Da.

Exemplary therapeutic agents for use in the devices and methods providedherein include, but are not limited to abatacept, teriparatide,emicizumab, pegfilgrastim, semaglutide, dulaglutide, sargramostim,ustekinumab, secukinumab, tocilizumab, vedolizumab, natalizumab,interferon beta-1a, denosumab, alirocumab, evolocumab, adalimumab,etanercept, golimumab, and certolizumab pegol; and biosimilars thereof;and glycosylation variants thereof. Additional exemplary drugs fordelivery using any of the devices or methods described herein includethose listed in Table 2.

TABLE 2 Drug Volume and Drug Potential Drug # capsules needed Storage(Brand Name) Dose concentration per equivalent dose^(a) temperatureHumira ® (adalimumab) 40, 80, 160 mg ~40 mg/0.4 mL 0.8-3.2 mL 2-8° C.2-8 Capsules 25° C. for up to 14 days Remicade ® (infliximab) 400 mgDiluted to ~4 mg/mL NA 2-8° C. 30° C. for up to 12 months Cimzia ®(certolizumabpegol) 400 mg ~200 mg/mL 4 mL 2-8° C. 10 Capsules 2 hrs atroom temp Embrel ® (etanercept) 50 mg ~50 mg/mL 2 mL 2-8° C. 5 Capsules25° C. for 14 days Lantis ® (insulin), sq 1 unit~0.0347 mg, 2-8° C.Novalog ® (insulin) density of crystal 30° C. for up is close to 1 g/cm³to 28 days Victoza ® (liraglutide) 1.2 mg ~6 mg/mL 0.4 mL 2-8° C. 1Capsules 30° C. for up to 30 days Bydureon ® (exenatide) 2 mg ~2 mg/0.6mL 1.2 mL 2-8° C. 3 Capsules 30° C. for up to 28 days (GHIH)(somatostatin) 0.48-2 mg Sandosatin ® (Octreotide) 100-500 mcg ~500mcg/mL 0.4-2 mL 2-8° C. 1-5 Capsules 30° C. for up to 14 days Avonex ®(interferon beta-la) 30 mcg ~30 mcg/0.5 mL 1 mL 2-8° C. 2.5 Capsules 30°C. for up to 30 days Tysabri ® (natalizumab) 300 mg ~2.69 mg/mL NA 2-8°C. Avastin ® (bevacizumab) 5 mg IFU: Do not administer NA 2-8° C. asbolus, IV Entyvio ® (Vedolizumab) 300 mg IFU: Do not administer NA asbolus, IV Fragmin ® (Dalteparin) 2500-18000 IU 5000 IU 0.6 mL Room Temp1.5 Capsules Rocephin ® (Ceftriaxone)(or 1 g ~350 mg/mL otherantimicrobials) Interferon alfa-2b 3-30 million IU ~50 million IU/mL0.12-1.2 mL 2-8° C., up to seven days at room temp <1-3 CapsulesNatpara ® (Parathyroid 50-100 mcg ~1 mg/mL <<1 Capsules 2-8° C. Hormone)(PTH) Genotropin ® Human Growth 0.2-2 mg ~5.3 mg/mL <1 Capsule 2-8° C. 4weeks Hormone (HGH) after reconstitution ^(a)Number of capsules assumesa drug reservoir of about 400 microliters sq: subcutaneous IFU:Instructions for use IU: International Unit

Therapeutics for Growth Disorders

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a therapeutic for treating a growthdisorder. In some embodiments, the growth disorder is a growth hormonedeficiency or disorder (GHD). In some embodiments, the GHD is acquired,congenital or idiopathic; or a combination thereof. In some embodiments,the GHD is a result of trauma, infection, radiation therapy or tumorgrowth. In some embodiments, the GHD is adult-onset GHD.

Exemplary therapeutics for treating growth disorders include, but arenot limited to, growth hormones, including, but not limited to,somatropin, lonapegsomatropin, YPEG-somatropin, efpegsomatropin, a humangrowth hormone (HGH), a recombinant HGH (rHGH), a PEGylated rHGH,somapacitan, somatrogon, genotropin, humatrope, norditropin, nutropin,omnitrope, serostim, TJ-101, ALT-P1, and JR-142; and biosimilars andfollow-on biologics thereof. In some embodiments, the growth hormone isan rHGH. Examples of suitable rHGHs include, but are not limited to,recombinant somatropin, e.g., genotropin, humatrope, norditropin,nutropin, omnitrope, serostim, Zomacton®, and Saizen®.

In some embodiments, the therapeutic suitable use with the devices andmethods described herein for treating a growth disorder is somatropin orbiosimilar or follow-on biologic thereof.

In some embodiments, the therapeutic suitable use with the devices andmethods described herein for treating a growth disorder is somapacitanor biosimilar or follow-on biologic thereof.

Therapeutics for Fibrosis

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a therapeutic for treating fibrosis. Insome embodiments, the therapeutic is a biological therapeutic. In someembodiments, the therapeutic is a small molecule. In some embodiments,the therapeutic is a non-oral therapeutic.

In some embodiments, the fibrosis is idiopathic pulmonary fibrosis. Insome embodiments, the fibrosis is cystic fibrosis.

Exemplary therapeutics for treating fibrosis for delivery using any ofthe devices or methods described herein include those listed in Table 3.

TABLE 3 Therapeutics adaptable for delivery via ingestible device forthe treatment of fibrosis Existing Formulation Technologies, ExemplaryPatent Drug Name/Class Methods of Administration LiteratureRituximab/Biological therapeutic; Infusion; Intravenous; SubcutaneousCN-101041907; Chimeric monoclonal antibody; CN-108676875; Recombinantprotein WO-08804936; WO-09411026 Abatacept (Orencia)/BiologicalFormulation powder; Freeze drying; WO-09300431 therapeutic; Antibodyfragment Infusion; Intravenous; Solution; Subcutaneous Tocilizumab(Actemra)/Biological Immunoglobulin-G; Infusion; WO-09219759therapeutic; Monoclonal antibody Intravenous; Solution humanized;Protein recombinant Rilonacept (Arcalyst)/Biological Formulation powder;Freeze drying; WO-00018932; therapeutic Subcutaneous WO-2004039951Pirfenidone/Small molecule therapeutic Aerosol formulation inhalant;WO-2012106382 Inhalant formulation BB-3/Small molecule therapeuticInfusion; Intravenous Ensifentrine/Small molecule therapeutic Aerosol;Inhalant formulation; Nasal WO-00058308 formulation; Suspension;Sustained release GSK-3008348/Small molecule therapeutic Inhalantformulation PLN-74809/Small molecule therapeutic Systemic AVID-200/Smallmolecule therapeutic Systemic WO-2017037634 RES-529 (Restorgenex)/Smallmolecule Ophthalmic WO-2007101247 therapeutic(intravitreal/subconjunctival) Fulvestrant/Small molecule therapeuticIntramuscular; Sustained release EP-00138504 Sodium pyruvate/Smallmolecule therapeutic Inhalant WO-09710818 Glutathione/ascorbicacid/bicarbonate Aerosol formulation inhalant WO-2014070769combination/Small molecule therapeutic CHF-6333/Small moleculetherapeutic Inhalant; Powder inhalantTherapeutics for Metabolic and/or Endocrine Diseases or Conditions

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a therapeutic for treating a metabolicor endocrine disease or condition. Examples of metabolic or endocrinediseases or conditions include, but are not limited to, diabetes,insulin resistance, hyperglycemia, hyperlipidemia, obesity, hepaticsteatosis, hyperinsulinemia, obstructive sleep apnea, non-alcoholicfatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liverfibrosis, liver cirrhosis, hypertension, pulmonary artery hypertension,primary sclerosing cholangitis, hyperlipoproteinemia type I, familialhypercholesterolemia, hypercholesterolemia, lipodystrophy, acromegaly,myocardial infarction, and thromboembolism; and combinations thereof. Insome embodiments, the metabolic or endocrine disease or condition isobesity.

Therapeutics suitable for treating a metabolic or endocrine disease orcondition include, but are not limited to, abatacept, aldesleukin,allogeneic human islets of langerhans, alogliptin, alpha-1 antitrypsin,anagliptin, benaglutide, berberine, bermekimab, bimagrumab, cibinetide,cotadutide, diabecell, diamyd, dutogliptin ebenatide, efpeglenatide,evogliptin, FSI-965, gemigliptin, glutazumab, gosogliptin, hinsbet,LAI-287, linagliptin, mecasermin, omarigliptin, otelixizumab,pegapamodutide, peg-loxenatide, pramlintide acetate, prolastin,protrans, rexmyelocel-t, saxagliptin, sitagliptin, somatostatin,teneligliptin, teplizumab, tirzepatide, trelagliptin, vildagliptin, andcombinations thereof. In some embodiments, therapeutic suitable fortreating a metabolic or endocrine disease or condition is selected frombortezomib, fulvestrant, bendamustine, itolizumab, golimumab,canakinumab, trichuris suis ova, NNC-0385-0434, NGM-282, BMS-986036, andremestemcel-L; and biosimilars thereof. In some embodiments, thetherapeutic suitable for treating a metabolic or endocrine disease orcondition is a proprotein convertase subtilisin/kexin type 9 (PCSK9)inhibitor. In some embodiments, the PCSK9 inhibitor is alirocumab orevolocumab. Other exemplary PCSK9 inhibitors for treating a metabolic orendocrine disease or disorder include those listed in Table 10.

Therapeutics for Diabetes

In some embodiments, the metabolic or endocrine disease or condition isdiabetes. In some embodiments, the diabetes is type I or type IIdiabetes. In some embodiments, the diabetes is an insulin dependentdiabetes. In some embodiments, the diabetes is a non-insulin dependentdiabetes. In some embodiments, the diabetes is gestational diabetes.

In some embodiments, the metabolic or endocrine disease or condition isdiabetes in combination with another disease or condition, including,but not limited to, diabetes with Alzheimer's disease, diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with NAFLD, diabetes with NASH, diabetes with NAFLDand NASH, and diabetes with a cardiovascular disease. In someembodiments, the diabetes is diabetes with obesity.

Therapeutics suitable for treating a metabolic or endocrine disease orcondition include, but are not limited to, an insulin, a glucagonreceptor agonist or a glucagon-like peptide-1 (GLP-1) receptor agonist,peptide YY ligand, and an amylin analong.

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a peptide YY ligand. The gut hormonepeptide YY (PYY), also known as peptide tyrosine tyrosine, is a 36-aminoacid peptide that is synthesized and released from specializedenteroendocrine cells called L-cells found predominantly within thedistal GI tract (see, e.g., Karra et al., J. Physiol. 587(Pt 1):19-25(2009)). In some embodiments, the peptide YY ligand is NN-9747, NN-9748,NN-9775 or any peptide YY ligand disclosed in WO 2016/198682, which isincorporated by reference herein in its entirety. In some embodiments,the peptide YY ligand is NN-9747 (PYY 1562, NNC0165-1562, NN-9748),analogue of the appetite-regulating hormone, PYY, which can be used formono- or combination treatment with the GLP-1 analogue semaglutide. Insome embodiments, NN-9747 or NN-9748 is administered subcutaneously qd.In some embodiments, NN-9747 is indicated for obesity. In October 2015,a phase I trial was initiated and completed in February 2017; N=93(Clinical Trials identifier: NCT02568306; source: Novo Nordisk AnnualReport 2018). In some embodiments, NN-9748 is indicated for diabetes. Insome embodiments, the peptide YY ligand is NN-9775 (NNC0165-1875), apeptide tyrosine 1875 analog (PYY 1875 analog), for the potential sctreatment of obesity and overweight. NN-9748 is an analogue of theappetite-regulating hormone, PYY, intended for mono- or combinationtreatment with the GLP-1 analogue semaglutide. In October 2018, afirst-human dose, phase I study of NNC0165-1875 as monotherapy and incombination with semaglutide was initiated; N=88 (clinical trialsidentifier: NCT03707990; source: Novo Nordisk Annual Report 2018). Insome embodiments, NN-9747 is the same drug substance as NN-9748.

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is an amylin analog. In some embodiments,the amylin analog is AM-833. In some embodiments, the metabolic orendocrine disease or condition is obesity or diabetes with obesity.

In some embodiments, the therapeutic is NNC0247-0829. In someembodiments, the metabolic or endocrine disease or condition is obesityor diabetes with obesity.

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a glucagon receptor agonist or aglucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments,the glucagon receptor agonist or the GLP-1 receptor agonist is glucagon.In some embodiments, the glucagon receptor agonist or the GLP-1 receptoragonist is NN-9277 (see, e.g., Brandt et al., J. Endocrinol.283(2):R109-R119 (2018)). In some embodiments, the glucagon receptoragonist or the GLP-1 receptor agonist is semaglutide; or a biosimilarthereof. In some embodiments, the glucagon receptor agonist or the GLP-1receptor agonist is dulaglutide; or a biosimilar thereof. In someembodiments, the glucagon receptor agonist or the GLP-1 receptor agonistis albiglutide; or a biosimilar thereof. In some embodiments, theglucagon receptor agonist or the GLP-1 receptor agonist is exenatide; ora biosimilar thereof. In some embodiments, the glucagon receptor agonistor the GLP-1 receptor agonist is liraglutide; or a biosimilar thereof.In some embodiments, the glucagon receptor agonist or the GLP-1 receptoragonist is lixisenatide; or a biosimilar thereof. In some embodiments,the glucagon receptor agonist or the GLP-1 receptor agonist isNNC-0090-2746.

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a therapeutic for treating diabetes.

In some embodiments, the therapeutic for treating diabetes that issuitable for use with the devices and methods described herein is aninsulin. In some embodiments, the insulin is selected from humaninsulin, insulin aspart, ultra-fast acting insulin aspart, insulindegludec, insulin detemir, insulin glargine, insulin glulisine, insulinlispro, and insulin tregopil.

In some embodiments, the therapeutic for treating diabetes that issuitable for use with the devices and methods described herein is adipeptidyl peptidase-4 inhibitor (DPP-4). DPP-4 inhibitors are oralhypoglycemics which are used to treat diabetes mellitus type-2. Thesedrugs include, but are not limited to: sitagliptin, vildagliptin,saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin,alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin,dutogliptin and berberine.

Exemplary therapeutics for treating diabetes for delivery using any ofthe devices or methods described herein include those listed in Table 4,and any combination thereof.

TABLE 4 Therapeutics adaptable for delivery via ingestible device forthe treatment of diabetes Existing Formulation Technologies, ExemplaryPatent Drug Name/Company Methods of Administration LiteratureDulaglutide Biological therapeutic; Immunoglobulin-G; WO2004110472Protein fusion; Solution; Subcutaneous Semaglutide/Novo NordiskBiological therapeutic; Peptide; WO2006097537; Subcutaneous; Oralsustained release; WO2012080471 Tablet Exenatide/Astrazeneca; Intarcia/Biological therapeutic; Intravenous WO09830231 Servier; PeptronSubcutaneous, Injectable controlled U.S. Pat. No. 05,424,286; release;Suspension; Sustained release; WO2004035754; Subcutaneous dmg implant;Drug WO00066629; combination WO2006083761; WO2008133908; WO2017200943;WO2017200944; WO2018075901 Insulin degludec Biological therapeutic;Cloning WO-2005012347 technology; Peptide; Solution; Subcutaneous;Sustained release Liraglutide Biological therapeutic; Peptide; ProteinWO-09727866; recombinant; Solution; Subcutaneous WO09808871; WO09832825;WO09943341; WO09943705; WO09943708; WO09947160 Insulin lispro/Sanofi;Gan & Lee Biological therapeutic; Biosimilar EP00383472;Pharmaceuticals; Eli Lilly; product; Follow on biologic; ProteinWO2004078239; Wanbang Biopharma; Adocia/ recombinant; DNA technology;CN104587455; Tonghua; Diasome Pharmaceuticals Infusion; Intravenous;Peptide; Quick WO2014076422 release; Solution; Subcutaneous; SuspensionInsulin glargine/Sanofi; Biocon/ Biological therapeutic; BiosimilarWO2004078239; Mylan/pisa/Fujifilm/GC product; Follow on biologic;EP00368187; Pharma; Eli Lilly/Boehringer; Protein recombinant; Solution;WO2011018745; Wockhardt; Gan & Lee Subcutaneous; Sustained releaseWO00210411; Pharmaceuticals/LG; Life WO2004050672; Sciences; Incepta;Getz Pharma; WO2012152175; Tonghua Dongbao; Jiangsu CN103439512; WanbangBiochemical CN104587455 Pharmaceutical Insulin aspart/Novo Nordisk;Biological therapeutic; Biosimilar WO2010149772; Gan & LeePharmaceuticals; product; Infusion; Intravenous; EP00214826; Sanofi;Zhunhai United Intramuscular; Protein recombinant; WO09426778;Laboratories; Dongbao Group; Subcutaneous; Quick release; Solution;CN103060335 Biocon/Mylan; Zhejiang Hisun Suspension; Ultra-fast actingPharmaceutical Insulin glargine + lixisenatide/ Biological therapeutic;Drug WO00104156 Sanofi/Zealand Pharma combination; Protein recombinant;Subcutaneous Insulin degludec + insulin aspart Biological therapeutic;Drug WO2005012347; combination; Peptide; Solution; WO2012080320Subcutaneous Insulin degludec + liraglutide/ Biological therapeutic;Drug WO09727866; Novo Nordisk combination; Peptide; Subcutaneous;WO09808871; Sustained release WO09832825; WO09943341; WO09943705;WO09943708; WO09947160; WO2005012347; WO2009063072 Insulin glulisineBiological therapeutic; Infusion; Intravenous; EP-00885961 Peptide;Solution; Subcutaneous Insulin detemir Biological therapeutic;Injectable controlled AU-00745983; release; Peptide; Proteinrecombinant; WO-09507931 Solution; Subcutaneous Alpha-1antitrypsin/Kamada/Shire Biological therapeutic; Intravenous; LiquidWO09856821 Insulin human/Eli Lilly Biological therapeutic; Proteinrecombinant; EP00037256 Solution; Subcutaneous; Suspension Pramlintideacetate Biological therapeutic; Peptide; Solution; WO09215317;Subcutaneous WO09310146 Albiglutide Biological therapeutic; Powder;Freeze US20080167238; drying; Liquid; Protein fusion; Protein WO03059934recombinant; Subcutaneous; Sustained release Insulin/Generex Biologicaltherapeutic; Buccal formulation WO00037053 systemic; Formulation aerosolunspecified; Protein recombinant Lixisenatide Biological therapeutic;Peptide; CN103467365; Subcutaneous CN106167528; WO00104156 ProlastinBiological therapeutic; Powder; Freeze EP-00097274 drying; Infusion;Intravenous; Peptide; Benaglutide Biological therapeutic; ProteinWO-03016349 recombinant; Subcutaneous Insulin Technosphere/SanofiBiological therapeutic; Inhalant; WO-09636314 Microparticle; PowderProtein recombinant Human insulin/Novo Nordisk Biological therapeutic;DNA technology, EP-00427296; A/S; Sanofi-Aventis; Bioton/ Follow onbiologic;Peptide; Subcutaneous; U.S. Pat. No. 04,029,642;Scigen/Actavis; Tonghua Suspension; Yeast recombinant; CloningWO-2013119132; Dongbao; Wockhardt; Geropharm; technology; Drug implant;Intravenous; CN-103439512; Horizon; Pharma/IBA Tech; SEDICO;Intramuscular; Protein recombinant; WO-2004024862; United LaboratoriesInternational Solution WO-00204515; Holdings; Square Pharmaceuticals;WO-09965941 Rechon Life Sciences Isophane insulin/Biocon Biologicaltherapeutic; Follow on biologic; WO-2010016069 Protein recombinant;Subcutaneous; Sustained release Insulin/Biocon; MJ Bioton LifeBiological therapeutic; Biosimilar WO-09426778; Science/MJBiopharm/Medipolis/ product; Follow on biologic; Protein CN-202530010;Marvel Life Sciences/Pharmstandard; recombinant; Quick release;Subcutaneous CN-202983284 Shenzhen Kexing Biotech; Hefei TianmaiBiotechnology; Valin Technologies Glucagon/Lilly Biological therapeutic;DNA technology; U.S. Pat. No. 04,033,941 Injectable; Parenteralformulation unspecified; Protein recombinant Mecasermin/FujisawaBiological therapeutic; Intravenous; WO-09103253 Protein recombinantShort acting insulin/Popular Biological therapeutic; Follow onPharmaceuticals biologic; Protein recombinant; Solution; Subcutaneous:Suspension Recombinant human insulin/Scigen Biological therapeutic;Protein recombinant; Transdermal; Transdermal high velocity particleformulation Rosinsulin Biological therapeutic; Subcutaneous; SuspensionSomatostatin/Lunan Pharmaceutical Biological therapeutic; Follow onbiologic; Intravenous; Peptide Insulin isophane/Wanbang Biologicaltherapeutic; Follow on CN-101173006 Biopharma; Shenzhen Kexing biologic;Protein recombinant; Biotech Solution; Subcutaneous Diabecell Biologicaltherapeutic; Cell therapy; WO-00152871 Intraperitoneal; Microparticle;Xenogeneic transplant Bermekimab Biological therapeutic;Immunoglobulin-G; WO-2009148575 Infusion; Intravenous; Monoclonalantibody human; Subcutaneous UNI-RE-4 Biological therapeutic; Powder;Liquid; CN-102370624 Parenteral formulation unspecified; Proteinrecombinant PEG-loxenatide Biological therapeutic; PEGylatedWO-2012155780 formulation; Peptide; Subcutaneous; Sustained releaseTirzepatide Biological therapeutic; PEGylated WO-2016111971 formulation;Peptide; Subcutaneous Efpeglenatide Antibody fragment; BiologicalWO-2008082274 therapeutic; Protein conjugated; Subcutaneous; Sustainedrelease Teplizumab Biological therapeutic; Infusion; WO-09428027Intravenous; Monoclonal antibody humanized; Subcutaneous Insulintregopil Biological therapeutic; Oral; Protein WO-2004083234 conjugatedInsulin/Alkermes/Eli Lilly Biological therapeutic; Infusion; Peptide;Subcutaneous Rexmyelocel-T Biological therapeutic; Cell therapy;WO-2018037134 Infusion; Intra-arterial; Leukocyte cell therapy RE-4Biological therapeutic; Protein recombinant; Subcutaneous; Systemicformulation unspecified Allogeneic human islets of Biologicaltherapeutic; Cell therapy; WO-2009006600 Langerhans/University ofSystemic formulation unspecified Illinois Pegapamodutide Biologicaltherapeutic; Injectable WO-2011087672 controlled release; PEGylatedformulation; Peptide; Subcutaneous; Sustained release LAI-287 Biologicaltherapeutic; Peptide; Subcutaneous; Sustained release; CLBS-03Biological therapeutic; Parenteral WO-2006031926 formulationunspecified; T-lymphocyte Insulin/Diabetology Biological therapeutic;Capsule; WO-2007093806 Enteric coated; Oral absorption enhancer; Oral;Peptide IONIS-gcgrrx Biological therapeutic; Infusion; WO-2008017081Intravenous; Oligonucleotide antisense; RNA antisense; SubcutaneousBimagrumab Biological therapeutic; Infusion; WO-2010125003 Intravenous;Monoclonal antibody human; Protein recombinant IONIS-ANGPTL3-lrxBiological therapeutic; Oligonucleotide WO-2015100394 antisense;Subcutaneous Aldesleukin/ILTOO Pharma Biological therapeutic; Proteinrecombinant; Subcutaneous HM-12525a Antibody conjugated; BiologicalWO-2012173422 therapeutic; Parenteral formulation unspecified; Peptide;Protein conjugated; Subcutaneous; Sustained release ORMD-0901 Biologicaltherapeutic; Capsule; Oral; WO-2009136392 Peptide Diamyd/Diamyd MedicalAntigen; Biological therapeutic; Parenteral formulation unspecified;Protein recombinant Pec-direct Biological therapeutic; Cell therapy;WO-2018089011 Drug implant; Pluripotent stem cell therapy GNBAC-1Biological therapeutic; Immunoglobulin-G; WO-2010003977 Infusion;Intravenous; Monoclonal antibody humanized; Protein recombinantInsulin/Oramed Biological therapeutic; Capsule; Oral; WO-2007029238Protein recombinant TOL-3021 Biological therapeutic; IntramuscularWO-2007044394 MPC-300-iv Allogenic stem cell therapy; BiologicalWO-2012000064 therapeutic; Infusion; Intravenous; Mesenchymal stem celltherapy Glutazumab Biological therapeutic; Monoclonal antibody; Proteinfusion; Subcutaneous Cotadutide Biological therapeutic; Peptide;WO-2015086686 Solution; Subcutaneous REMD-477 Biological therapeutic;Monoclonal WO-2015189698 antibody human; Subcutaneous PEC-encapBiological therapeutic; Cell therapy; WO-2005063971 Pluripotent stemcell therapy; Subcutaneous drug implant Cibinetide/Araim Biologicaltherapeutic; Infusion; WO-2007019545; Intravenous; Peptide; SubcutaneousWO-2009094172 LY-3209590 Biological therapeutic; Peptide; SubcutaneousOtelixizumab Biological therapeutic; Infusion; WO-09319196 Intravenous;Monoclonal antibody humanized; Subcutaneous AG-019 Bacteria recombinant;Biological WO-2007063075 therapeutic; Capsule; Oral; Peptide GABA +antigen based therapy/ Antigen; Biological therapeutic; DrugWO-2017058074 Diamyd combination; Oral; Tablet Allogeneic humanmesenchymal Allogenic stem cell therapy; Biological WO-2018089752 stemcells/Longeveron therapeutic; Infusion; Intravenous; Local formulationunspecified; Mesenchymal stem cell therapy Cell therapy/SernovaBiological therapeutic; Cell therapy; WO-09528167 Subcutaneous InsulinDiabetology Biological therapeutic; Capsule; WO-2007093806 Entericcoated; Oral absorption enhancer; Oral; Peptide PB-119 Biologicaltherapeutic; PEGylated WO-2010121559 formulation; Peptide; SubcutaneousIonis-DGAT2Rx Biological therapeutic; Oligonucleotide WO-2017011276antisense; Subcutaneous Abatacept/NIDDK Biological therapeutic;Immunoglobulin-G; WO-2013177505 Intravenous; Protein fusion EbenatideBiological therapeutic; Protein conjugated; WO-2007053946 Subcutaneous;Sustained release Protrans Allogenic stem cell therapy; Biologicaltherapeutic; Infusion; Intravenous; Mesenchymal stem cell therapy;Umbilical cord stem cell therapy Hinsbet Biological therapeutic;Injectable; WO-2010122385 Parenteral formulation unspecified; Peptide;Protein recombinant; Quick release Glucagon-like peptide-1 analog/Imaging; Infusion; Peptide; Radiolabeling; Radboud University Systemicformulation unspecified Insulin (long-acting iv, hepatic Biologicaltherapeutic; Nanoparticle WO-2011022396 directed vesicles (HDV))formulation injectable; Parenteral Diasome Pharmaceuticals formulationunspecified; Protein recombinant Human insulin/Dance/ Aerosolformulation inhalant; Biological WO-2011088070 Harmony/Dongbaotherapeutic; Inhalant; Protein recombinant Anti-IL-21 + liraglutide/Biological therapeutic; Intravenous; WO-2012098113 Novo NordiskMonoclonal antibody human; Subcutaneous NNC-0090-2746 Biologicaltherapeutic; PEGylated WO-2010096052 formulation; Peptide; SubcutaneousBIOD-531 Biological therapeutic; Parenteral formulation unspecified;Protein recombinant; Subcutaneous Allogenic umbilical cord-derivedAllogenic stem cell therapy; Biological mesenchymal stem cell therapy/therapeutic; Intravenous; Mesenchymal Nanjing University stem celltherapy Insulin/Diasome Pharmaceuticals Biological therapeutic;Nanoparticle formulation injectable; Intravenous; Capsule; Oral;Nanoparticle formulation oral; Protein recombinant

Therapeutics for NASH/NAFLD

In some embodiments, the disease or condition is NASH and/or NAFLD. Insome embodiments, the therapeutic suitable for use with the devices andmethods described herein is a therapeutic for treating non-alcoholicsteatohepatitis (NASH) and/or non-alcoholic fatty liver disease (NAFLD).NASH (non-alcoholic steatohepatitis) is a fatty liver disease affectingas many as 12% of the U.S. adults. There are many potential drugs totreat this disease illustrated by: selonsertib, cenicriviroc,elafibranor, ocaliva, tropifexor, firocostat, cilofexor, aramchol,ARX618, BI 1467335, DS 102, EDP-305, emricasan, gemcabene, GR-MD-02,GRI-0621, GS-0976, GS-9674, IMM-124E, IONIS-DGAT2Rx, IVA-337, lipaglyn,LJN452, LLMB763, MGL-3196, MN-001, MSDC-0602K, NC101, NGM282, NGM313,NS-0200, ozempic, PF-05221304, PF-06835919, remogliflozin etabonate,SHP626, TVB-2640, VK2809, butanoic acid, CER209, evogliptin, DUR928,MK-4074, OPRX-106, PF06865571, PF06882961, PXS-5382A, RG-125, RYI-018,seladelpar, SGM-1019 and TVB-2640. In some embodiments, the therapeuticsuitable for use with the devices and methods described herein isselected from the therapeutic agent is selected from the groupconsisting of selonsertib, cenicriviroc, elafibinor, ocaliva,tropifexor, firocostat and cilofexor. These represent several biologicalmechanisms. A combination of multiple drugs may be required. In someembodiments, the drug is selected from selonsertib, cenicriviroc,elafibinor, ocaliva, tropifexor, firocostat and cilofexor.

Exemplary therapeutics for treating NASH and/or NAFLD for delivery usingany of the devices or methods described herein include those listed inTable 5.

TABLE 5 Therapeutics adaptable for delivery via ingestible device forthe treatment of NASH/NAFLD Existing Formulation Technologies ExemplaryPatent Drug Name and Methods of Administration Literature NGM-282Biological therapeutic; Protein recombinant; Subcutaneous WO-2013006486IONIS-ANGPTL3-LRx Biological therapeutic; Oligonucleotide antisense;Subcutaneous WO-2015100394 Insulin/Oramed Biological therapeutic;Capsule; Oral; Protein recombinant WO-2007029238 BMS-986036 Biologicaltherapeutic; PEGylated formulation; Protein WO-2008121563 recombinant;Subcutaneous IMM-124-E Antibody polyclonal; Biological therapeutic;Powder; WO-2010125565 Immunoglobulin-G; Oral Semaglutide/Novo NordiskBiological therapeutic; Peptide; Subcutaneous; Sustained releaseIONIS-DGAT2Rx Biological therapeutic; Oligonucleotide antisense;Subcutaneous WO-2017011276

Therapeutics for Rheumatoid Arthritis

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a therapeutic for treating rheumatoidarthritis. Exemplary therapeutics for treating rheumatoid arthritis fordelivery using any of the devices or methods described herein includethose listed in Table 6.

TABLE 6 Therapeutics adaptable for delivery via ingestible device forthe treatment of rheumatoid arthritis Existing Formulation Technologies,Exemplary Patent Drug Name/Company Methods of Administration LiteratureCertolizumab pegol Antibody fragment; Biological WO-00194585therapeutic; Powder; Freeze drying; Monoclonal antibody humanized;PEGylated formulation; Protein conjugated; Protein recombinant;Solution; Subcutaneous Corticotropin/Mallinckrodt Biologicaltherapeutic; Gel; Injectable WO-2011143152 controlled release;Intramuscular; Peptide; Subcutaneous; Sustained releaseCiclosporin/Novartis; Chong Kun Biological therapeutic; Capsule;Emulsion; GB-01491509; Dang Infusion; Intravenous; Oral; Oral gel; U.S.Pat. No. 06,306,825; Peptide; Solution WO-09522982Etanercept/Sandoz/Hexal; Biological therapeutic; Biosimilar product;EP-00417563; Zhejiang Hisun Pharmaceutical; Cell culture; Powder; Freezedrying; EP-00835939; Shanghai Citic Pacific Guojian Immunoglobulin-G;Liquid; Protein fusion; WO-09013575; Pharmaceutical; Samsung Bioepis;Solution; Subcutaneous Shanghai Celgen Biopharmaceutical; WO-09103553;LG Chem/Mochida; Viropro; Aryogen; WO-2014060551; AXXO; Amega; Pfizer;Hanwha; WO-00036092; Lupin; Coherus Biosciences; Qilu WO-2014102814;Pharmaceutical WO-2012165917; WO-2010099153; WO-2014064637;WO-2013059405 Abatacept Biological therapeutic; Powder; FreezeWO-09300431 drying; Immunoglobulin-G; Infusion; Intravenous; Proteinconjugated; Protein fusion; Solution; SubcutaneousAdalimumab/Actavis/Amgen/ Biological therapeutic; Biosimilar product;U.S. Pat. No. 07,517,963; Daiichi Sankyo/Orion; SamsungImmunoglobulin-G; DNA technology; US-20130122018; Bioepis; Sandoz; ZydusMonoclonal antibody human; Protein WO-09102078; Cadilla/GlenmarkPharmaceuticals; recombinant; Solution; Subcutaneous WO-09729131;Fujifilm Kyowa Kirin Biologics/ WO-2016019726; Mylan; Hetero; RelianceLife WO-2018119142; Sciences, AXXO; Boehringer WO-2016000813; Ingelheim;Zhejiang Hisun WO-2015007912; Pharmaceutical; Pfizer; WO-2014207763;Innovent Biologies; Fresenius; WO-2013021148; Shanghai Henlius Biotech;Bio- WO-2013186230; Thera Solutions; Celltrion; WO-2014099636;Momenta/Shire; LG Life Sciences WO-2019024783; WO-2013181577;WO-2018169348 Tocilizumab/Roche/Chugai; Bio- Biological therapeutic;Biosimilar; WO-00117542; Thera Solutions Monoclonal antibody humanized;Protein WO-09219759; recombinant; Subcutaneous; Infusion; WO-2016103093Intravenous; Solution Itolizumab Biological therapeutic; Intravenous;WO-09719111; Monoclonal antibody humanized; Subcutaneous WO-2009113083Infliximab/Pfizer/Sandoz; Biological therapeutic; Biosimilar product;U.S. Pat. No. 07,517,963; Samsung Bioepis/Merck & Co; Cell culturetechnique; Chimeric monoclonal US-20050255104;Celltrion/NipponKayaku/Hospira/ antibody; Protein recombinant; Powder;WO-09102078; Orion/EGIS Gyogyszergyar; Freeze drying; Immunoglobulin-G;Infusion; WO-09216553; Bionovis/Fiocruz/IVB; Aprogen/ Intra-articular;Intravenous WO-03045400; Nichi-Iko Pharm/Sanofi; WO-2006122187;Celltrion Healthcare; Amgen; WO-2006093397; BiomabPharmaceuticals;Mabtech/ WO-2009026122; Sorrento; Biocad; Genor WO-2011103700;WO-2017120614 Sarilumab Biological therapeutic; Monoclonal WO-2007143168antibody human; Solution; Subcutaneous Rituximab/Celltrion/ Biologicaltherapeutic; Biosimilar product; CN-101041907; Mundipharm/Teva/NipponChimeric monoclonal antibody; WO-09411026; Kayaku; Sandoz; Aryogen;Immunoglobulin-G; Infusion; Intravenous; WO-08804936; Reliance LifeSciences, AXXO; Protein recombinant; Subcutaneous CN-108676875; Biocad;Hetero; Dr Reddy's/CFR WO-2006093397; Pharmaceuticals/Cinnagen; IntasWO-00027428; Biopharmaceuticals; Shanghai WO-2009007993; Henlius;Mabion; Allergan/Amgen WO-2013126813 Golimumab/Johnson & JohnsonBiological therapeutic; Immunoglobulin-G; U.S. Pat. No. 07,691,378;Monoclonal antibody human; Solution; WO-00212502; Subcutaneous;Infusion; Intravenous WO-2018140121 Canakinumab Biological therapeutic;DNA technology; WO-00216436 Powder; Freeze drying; Immunoglobulin-G;Infusion; Intra-articular; Liquid; Monoclonal antibody human; Proteinrecombinant; Subcutaneous Opinercept Biological therapeutic; Freezedrying; Protein fusion; Solution; Subcutaneous Trichuris suis ova,ovamed/ Biological therapeutic; Cell therapy; WO-09933479 DrFalk/Fortress Biotech Oral; Oral suspension Anakinra/AXXO Biologicaltherapeutic; Follow on biologic; WO-08911540 Intramuscular; Intravenous;Peptide; Protein recombinant; Subcutaneous Interleukin-2/ChangchunBiological therapeutic; Follow on biologic; WO-2011106991 Institute ofBiological Products; Injectable; Parenteral formulation Changchunchangsheng Gene unspecified; Protein recombinant; Pharmaceutical;Guangdong Subcutaneous; Freeze drying; Intratumoral; Weilun BiologicalProducts; Intravenous Beijing SL Pharmaceutical; Shandong QuangangPharmaceutical; Shenzhen Neptunus Cartistem Biological therapeutic;Mesenchymal stem WO-2010131917 cell therapy; Parenteral formulationunspecified Interferon gamma/Livzon Biological therapeutic; Follow onbiologic; CN-01799626 Pharmaceutical Group; Shanghai Freeze drying;Intramuscular; Protein Chemo Wanbang Biopharma recombinant; SubcutaneousKa shu ning Biological therapeutic; Intramuscular; Oligosaccharide;Solution VAY-736 Biological therapeutic; Immunoglobulin-G; WO-2010007082Infusion; Monoclonal antibody human; Subcutaneous Tadekinig alfa/AB2 BioBiological therapeutic; Protein WO-2015032932 recombinant; SubcutaneousOlokizumab Biological therapeutic; Intravenous; WO-2007066082 Monoclonalantibody humanized; Subcutaneous Recombinant human CD22 Biologicaltherapeutic; Infusion; WO-2013188864 monoclonal antibody, Lonn RyonnIntravenous; Monoclonal antibody Pharma/sinomab Bioscience RCT-18Biological therapeutic; Monoclonal antibody humanized; Protein fusion;Protein recombinant; Subcutaneous Ocaratuzumab Biological therapeutic;Immunoglobulin-G; WO-2004103404 Infusion; Intravenous; Monoclonalantibody humanized; Protein recombinant Otilimab Biological therapeutic;Immunoglobulin-G; WO-2006122797 Infusion; Intravenous; Monoclonalantibody human; Protein recombinant; Subcutaneous E-6011/EA PharmaBiological therapeutic; Monoclonal EP-03159007 antibody humanized;Subcutaneous MPC-300-iv Allogenic stem cell therapy; BiologicalWO-2012000064 therapeutic; Infusion; Intravenous; Mesenchymal stem celltherapy ASP-5094 Biological therapeutic; Intravenous; Monoclonalantibody human; Systemic formulation unspecified Cibinetide/AraimBiological therapeutic; Infusion; WO-2007019545; Intravenous; Peptide;Subcutaneous WO-2009094172 Pf-06687234 Biological therapeutic;Intravenous; WO-2009056268 Protein fusion; Subcutaneous ^(99m)Tclabelled annexin V-128/ Imaging; Intravenous; Protein WO-2018069409Advanced Accelerator recombinant; Radiolabeling Applications Cx-611Adipose stem cell therapy; Allogenic stem WO-2006037649 cell therapy;Biological therapeutic; Intravenous; Mesenchymal stem cell therapyCreaVax-RA Autoantigen; Biological therapeutic; Cell WO-2008102937therapy; Parenteral formulation unspecified; Subcutaneous AMG-592Biological therapeutic; Protein fusion; WO-2014153063 Proteinrecombinant; Subcutaneous Ozoralizumab Biological therapeutic;Intravenous; WO-2006122786; Monoclonal antibody humanized; WO-2010077422Subcutaneous NI-0101 Biological therapeutic; Immunoglobulin-G;WO-2009101479 Infusion; Intravenous; Monoclonal antibody humanizedPRTX-100 Biological therapeutic; Infusion; WO-03086317 IntravenousVobarilizumab/Ablynx Biological therapeutic; Multivalent WO-2008020079antibody; Subcutaneous BCD-089 Biological therapeutic; MonoclonalWO-2018034597 antibody human; Subcutaneous Theralizumab Biologicaltherapeutic; Immunoglobulin-G; WO-09854225 Infusion; Intravenous;Monoclonal antibody humanized AT-132 Biological therapeutic; MonoclonalWO-2012116595 antibody humanized; Subcutaneous Oralgam Biologicaltherapeutic; Immunoglobulin; WO-03028668 Oral INV-103 Biologicaltherapeutic; Intravenous; WO-2004041300 Protein recombinant;Subcutaneous Umbilical cord-derived Biological therapeutic; Intravenousmesenchymal stem cells/ Mesenchymal stem cell therapyAlliancells/Zhongyuan Union

Therapeutics for IBD

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a therapeutic for treating inflammatorybowel disease (IBD). Exemplary therapeutics for treating IBD fordelivery using any of the devices or methods described herein includethose listed in Table 7.

TABLE 7 Therapeutics adaptable for delivery via ingestible device forthe treatment of IBD Existing Formulation Technologies and ExemplaryPatent Drug Name/Company Methods of Administration LiteratureCertolizumab pegol Biological therapeutic; Powder; Freeze drying;WO-00194585 Monoclonal antibody humanized; PEGylated formulation;Protein conjugated; Protein recombinant; Solution; SubcutaneousUstekinumab Biological therapeutic; Cell culture; WO-00212500Immunoglobulin-G; Infusion; Intravenous; Monoclonal antibody human;Subcutaneous Adalimumab/Actavis/ Biological therapeutic; DNA technology;U.S. Pat. No. 07,517,963; Amgen/Daiichi Sankyo/ Biosimilar product;Immunoglobulin-G; US-20130122018; Orion; Samsung Bioepis; Monoclonalantibody human; Protein WO-09102078; Sandoz; Fujifilm Kyowa recombinant;Solution; Subcutaneous WO-09729131; Kirin Biologics/Mylan;WO-2016019726; CinnaGen; Reliance Life WO-2018119142; Sciences;Boehringer WO-2016000813; Ingelheim; Fresenius; Bio- WO-2015007912;Thera Solutions WO-2013021148; WO-2013186230; WO-2014099636;WO-2019024783 Vedolizumab Biological therapeutic; Powder; Freeze drying;WO-09806248 Immunoglobulin-G; Infusion; Intravenous; Monoclonal antibodyhumanized; Subcutaneous Infliximab/Celltrion/Nippon Biologicaltherapeutic; Cell culture technique; U.S. Pat. No. 07,517,963;Kayaku/Hospira/Orion/EGIS Biosimilar product; Protein recombinant;US-20050255104; Gyogyszergyar; Chimeric monoclonal antibody; Powder;Freeze WO-09102078; Pfizer/Sandoz; Bionovis/ drying; Immunoglobulin-G;Infusion; Intra- WO-09216553; Fiocruz/IVB Samsung articular; IntravenousWO-2006093397; Bioepis/Merck & Co; WO-03045400; Aprogen/Nichi-Iko Pharm/WO-2006122187 Sanofi; AXXO Natalizumab Biological therapeutic; Cellculture technique; WO-09519790 Immunoglobulin-G; Infusion; Intravenous;Monoclonal antibody humanized; Solution; Subcutaneous GuselkumabBiological therapeutic; Intravenous; WO-2007005955; Monoclonal antibodyhuman; Subcutaneous WO-2007076524 Golimumab Biological therapeutic;Immunoglobulin-G; U.S. Pat. No. 07,691,378; Monoclonal antibody human;Monthly dosing; WO-00212502 Solution; Subcutaneous Adipose-derived stemcell Adipose stem cell therapy; Aerosol formulation U.S. Pat. No.07,887,795; therapy (Celution System), dermatological; Autologous stemcell therapy; WO-03053346 Cytori Biological therapeutic; Dermatological;Infusion; Intravenous; Subcutaneous Remestemcel-L Allogenic stem celltherapy; Biological WO-09623058 therapeutic; Haematopoietic stem celltherapy; Intravenous; Mesenchymal stem cell therapy Anakinra Biologicaltherapeutic; Intramuscular; WO-08911540 Intravenous; Peptide; Proteinrecombinant; Subcutaneous Clostridium butyricum/ Biological therapeutic;Capsule; Oral U.S. Pat. No. 08,092,793 Qingdao Eastsea PharmaceuticalsBacillus Licheniformis, Biological therapeutic; Capsule; Oral NortheastPharmaceutical Group Shenyang No. 1 Pharmaceutical Co. RisankizumabBiological therapeutic; Immunoglobulin-G; WO-2012061448 Infusion;Intravenous; Monoclonal antibody humanized; Subcutaneous AlicaforsenBiological therapeutic; Oligonucleotide WO-09405333 antisense; Rectalformulation; Rectal formulation local Bimekizumab Biologicaltherapeutic; Immunoglobulin-G; WO-2008047134 Infusion; Intravenous;Monoclonal antibody humanized; Subcutaneous Mirikizumab Biologicaltherapeutic; Humanized antibody; WO-2014137962 Immunoglobulin-G;Intravenous; Subcutaneous BI-655130 Biological therapeutic;Immunoglobulin-G; WO-2013074569 Infusion; Intravenous; Monoclonalantibody humanized Brazikumab Biological therapeutic; Infusion;Intravenous; WO-2011056600 Monoclonal antibody human; SubcutaneousSHP-647 Biological therapeutic; Immunoglobulin-G; WO-2019014572Intravenous; Monoclonal antibody human; Subcutaneous CobitolimodBiological therapeutic; Oligonucleotide; Rectal; WO-09535032; Rectalformulation local WO-2010053430 Umbilical cord blood- Biologicaltherapeutic; Parenteral formulation WO-2016048107 derived stem celltherapy, unspecified; Umbilical cord stem cell therapy Kang StemBiotech/ Daewoong Etrolizumab Biological therapeutic; Immunoglobulin-G;WO-2006026759 Intravenous; Monoclonal antibody humanized; Proteinrecombinant; Subcutaneous BBT-401 Biological therapeutic; Capsule; Oral;Peptide SER-287 Bacterium novel; Biological therapeutic; WO-2017008026Capsule; Cell therapy; Oral KHK-4083 Biological therapeutic;Intravenous; WO-2007062245 Monoclonal antibody human; SubcutaneousAbGn-168H Biological therapeutic; Infusion; Intravenous; EP-01663290;Monoclonal antibody humanized WO-03013603 RG-7880 Biologicaltherapeutic; Immunoglobulin; WO-2005009238 Infusion; Intravenous;Protein fusion; Protein recombinant; Subcutaneous SB-012 Biologicaltherapeutic; DNA technology; Oligonucleotide antisense; Rectalformulation; Rectal formulation local Olamkicept Biological therapeutic;Intravenous; Protein WO-2007071449 fusion Bertilimumab Biologicaltherapeutic; Immunoglobulin-G; WO-00166754 Infusion; Intravenous;Monoclonal antibody human; Parenteral formulation unspecified;Subcutaneous PF-06480605 Biological therapeutic; Intravenous;Subcutaneous PF-06687234 Antibody fragment; Biological therapeutic;WO-2009056268 Intravenous; Protein fusion; Subcutaneous IBP-9414Biological therapeutic; Natural product; Oral WO-2016113363Molgramostim + Antibiotic; Biological therapeutic; Capsule; fosfomycin +Follow on biological product; Local carbapenem)/Reponex formulationunspecified; Oral; Peptide; Protein recombinant; Rectal formulation;Rectal formulation local STNM-01 Biological therapeutic; Injectable;Local WO-2008020489 formulation unspecified; Oligonucleotide; Parenteralformulation unspecified; Transmucosal Adrenomedullin/UniversityBiological therapeutic; Intravenous; Parenteral of Miyazaki formulationunspecified; Peptide Tulinercept Antibody fragment; Biologicaltherapeutic; WO-2014136113 Immunoglobulin-G; Oral; Protein fusionE-6011, EA Pharma Biological therapeutic; Intravenous; EP-03211007Monoclonal antibody STP-206 Biological therapeutic; Natural product;WO-2005032567 Parenteral formulation unspecified FFP-104 Biologicaltherapeutic; Monoclonal antibody; WO-09858678 Parenteral formulationunspecified Ciclosporin/Sublimity Biological therapeutic; Capsule; Oralcontrolled WO-2004084870 Therapeutics/Dr Falk release; Oral; PeptidePharma AEVI-002 Biological therapeutic; Monoclonal antibodyWO-2013148350 human; Parenteral formulation unspecified; SubcutaneousMidismase Biological therapeutic; Controlled release; EP-00406804Infusion; Intravenous; Protein conjugated V-565 Antibody; Biologicaltherapeutic; Oral; Protein WO-2016156465; recombinant; TabletWO-2016156468; WO-2016156474; WO-2016156475

Therapeutics for Hemophilia

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a therapeutic for treating hemophilia.In some embodiments, the hemophilia is hemophilia A, hemophilia B, orVon Willebrand disease.

In some embodiments, the therapeutic for treating hemophilia is analternative coagulation promotor (ACP). In some embodiments, the ACP isan anti-tissue factor pathway inhibitor (anti-TFPI). Exemplaryanti-TFPIs include, but are not limited to, concizumab, MG-1113A (GCPharma, Gyeonggi-do, South Korea), marstacimab (PF-6741086) orBAY-1093884; or biosimilars thereof. In some embodiments, the anti-TFPIis concizumab or a biosimilar thereof.

In some embodiments, the therapeutic for treating hemophilia is a factorVIII mimetic. In some embodiments, the factor VIII mimetic is emicizumabor a biosimilar thereof.

In some embodiments, the therapeutic for treating hemophilia is selectedfrom albutrepenonacog alfa, AMT-061, beroctocog alpha, betafact,BIVV-001, BS027125, byclot, catridecacog, clotnine, dalcinonacog alfa,damoctocog alfa pegol, DTX-201, eftrenonacog alfa, eptacog alfa, FactorVIII, Factor IX, Factor X, fidanacogene elaparvovec, fitusiran,FLT-180a, hemoleven, lonoctocog alfa, LR-769, marzeptacog alfa, monofix,moroctocog alfa, NIBX-2101, nonacog alfa, nonacog beta pegol, octocogalfa, OPK-88005, recolyl, recombinate, rurioctocog alfa pegol,simoctocog alfa, SHP-654, SB-525, SPK-8011, SPK-8016, SCT-800,AAV2/8-HLP-FVIII-v3, susoctocog alfa, trenonacog alfa and valoctocogeneroxaparvovec; and biosimilars thereof.

In some embodiments, the therapeutic for treating hemophilia is arecombinant factor VIIa. Exemplary recombinant factor VIIa includeOPK-88005 (OPKO Health, Miami, Fla.) and LR-769 (see, e.g., Chevreux etal., Haemophilia 23(4):e324-e334 (2017)). Additional exemplarytherapeutics for treating hemophilia for delivery using any of thedevices or methods described herein include those listed in Table 8.

TABLE 8 Therapeutics adaptable for delivery via ingestible device forthe treatment of hemophilia Existing Formulation Drug Name/ Technologiesand Exemplary Patent Class/Company Methods of Administration LiteratureDamoctocog alfa pegol Biological therapeutic; Infusion; Intravenous;WO-2010083536 PEGylated formulation; Protein recombinant; Sustainedrelease Efmoroctocog alfa Antibody fragment; Biological therapeutic;Cell WO-2011069164 culture technique; Powder; Freeze drying;Immunoglobulin-G; Injectable controlled release; Protein fusion; Proteinrecombinant Octocog alfa/Bayer; Biological therapeutic; Plasma-free,sucrose- EP-00160457; Baxalta; Genentech/ formulated; Intravenous;Peptide; Protein EP-00818204; Bayer/Aventis recombinant; Powder; Freezedrying; EP-00152746; Glycoprotein; Infusion EP-00160457; EP-00818204Rurioctocog alfa pegol Biological therapeutic; Formulation powder; U.S.Pat. No. 07,884,075; Freeze drying; Intravenous; PEGylatedWO-2004075923; formulation; Protein recombinant; Sustained WO-2006071801release Albutrepenonacog alfa Biological therapeutic; Infusion;Intravenous; WO-00177137; Protein fusion; Protein recombinant; SustainedWO-2007144173 release Lonoctocog alfa Biological therapeutic; Infusion;Parenteral WO-2004067566 formulation unspecified; Protein recombinantTrenonacog alfa Biological therapeutic; Freeze drying; Infusion;WO-2009082648 Intravenous; Protein recombinant Nonacog gamma Biologicaltherapeutic; Cloning technology; WO-2011135071 Powder; Freeze drying;Infusion; Intravenous; Protein recombinant; Solution Turoctocogalfa/Novo Biological therapeutic; Powder; Freeze drying; WO-2007055789;Nordisk Intravenous; PEGylated; Sustained release; WO-2009108806 Proteinrecombinant Von Willebrand/Factor Biological therapeutic; Intravenous;Peptide EP-00144709 VIII therapy/Alpha Therapeutic Emicizumab Biologicaltherapeutic; Immunoglobulin-G; WO-2005035753; Monoclonal antibodyhumanized; Multivalent WO-2012067176 monoclonal antibody; Proteinrecombinant; Subcutaneous Nonacog alfa/IBC Biological therapeutic;Biosimilar product; EP-00430930 Generium/CJSC Powder; Freeze drying;Infusion; Intravenous; Generium/Stragen Peptide; Protein recombinantNonacog beta pegol Biological therapeutic; Powder; Freeze drying;WO-03031464; Glycoprotein; Infusion; Intravenous; PEGylated WO-03045980;formulation; Protein recombinant; Sustained WO-03046150; releaseWO-2004099231; WO-2006127896; WO-2008060780 Eptacog alfa (activated)/Biological therapeutic; Biosimilar product; EP-00200421; Aryogen; IBCPowder; Freeze drying; Intravenous; Protein WO-2008155509; Generium/CJSCrecombinant; Solution; Transgenic animal Generium/Stragen; RevoBiologics/LFB Factor VIII concentrate Biological therapeutic; Bloodconstituents; (albumin-free), CSL Infusion; Intravenous Simoctocog alfaBiological therapeutic; Infusion; Intravenous; WO-00170968 Proteinrecombinant Eftrenonacog alfa Antibody fragment; Biological therapeutic;WO-2004101740; Powder; Freeze drying; Immunoglobulin-G; WO-2007112005Injectable controlled release; Intravenous; Protein fusion Susoctocogalfa Biological therapeutic; Formulation powder; WO-09749725 Freezedrying; Infusion; Intravenous; Protein recombinant Factor VIII follow-onBiological therapeutic; Follow on biological biologic, AXXO product;Intravenous; Protein recombinant Moroctocog alfa Biological therapeutic;Injectable; Parenteral WO-08606101 formulation unspecified; Proteinrecombinant Factor VIII (plasma- Biological therapeutic; Intravenous;Peptide; WO-09110439; derived)/Octapharma/ Blood constituents; Freezedrying; Infusion U.S. Pat. No. 03,631,018 Shire Factor XIII concentrate,Biological therapeutic; Intravenous; Peptide WO-2005079839 CSL MonofixBiological therapeutic; Intravenous; Peptide EP-00118256 HemolevenBiological therapeutic; Blood constituents; Parenteral formulationunspecified; Peptide; Systemic formulation unspecified CatridecacogBiological therapeutic; Formulation powder; EP-00268772 Freeze drying;Intravenous; Protein recombinant Byclot Biological therapeutic; Drugcombination; Freeze JP-04046377 drying; Intravenous; Peptide FactorVIII/von Biological therapeutic; Infusion; Intravenous; WO-2008151817Willebrand Factor Peptide complex, CSL Recombinant moroctocog Biologicaltherapeutic; Powder; Freeze drying; WO-08606101 alfa (plasma/albumin-Glycoprotein; Infusion; Intravenous; Protein free), Wyeth recombinantBeroctocog alpha Biological therapeutic; Infusion; Intravenous;EP-01712223 (albumin-free)/GC Protein recombinant Pharma Moroctocog alfaBiological therapeutic; Biosimilar product; biosimilar, IBC Intravenous;Protein recombinant Generium/CJSC Generium/Stragen Beroctocog alfaBiological therapeutic; Infusion; Intravenous; KR-00251286 Proteinrecombinant Factor VIII concentracte, Blood constituents; Infusion;Intravenous; Small Kedrion Biopharma molecule therapeutic Factor XIconcentrate, Blood constituents; Parenteral formulation CSL Behringunspecified; Small molecule therapeutic; Systemic formulationunspecified Factor VIII/Tonrol Biological therapeutic; Bloodconstituents; WO-08403628 Biopharmaceutical; Novo Intravenous; PeptideNordisk Recombinate Biological therapeutic; Powder; Freeze drying;WO-08501961 Glycoprotein; Intravenous; Protein recombinant FactorXP/Behring Biological therapeutic; Freeze drying; Intravenous; PeptideHuman coagulation Biological therapeutic; Blood constituents;WO-2015114664 factor VIII, Hemarus Intravenous; Protein recombinantClotnine Biological therapeutic; Blood constituents; WO-2015114664Intravenous; Protein recombinant Betafact Biological therapeutic;Peptide; Systemic EP-00317376 formulation unspecified Factor VIIIfollow-on Biological therapeutic; Follow on biological CN-102295696biologic, Shandong product; Parenteral formulation unspecified; TaibangBiological Protein recombinant Products Moroctocog alfa follow-Biological therapeutic; Follow on biological on biologic, Amega product;Parenteral formulation unspecified; Protein recombinant Plasma derivedfactor Biological therapeutic; Liposome; PEGylated WO-09955306 VIII(pegylated formulation; Protein conjugated liposomal (neclip), RecolyHuman prothrombin Biological therapeutic; Blood constituents; complexconcentrate Infusion; Intravenous; Peptide (plasma-derived), NanyueBiopharming; Shanxi Kangbao Biological Products Factor IX, ShandongBiological therapeutic; Intravenous; Peptide Taibang Biological ProductsFactor VIII biosimilar, Biological therapeutic; Biosimilar product;Shanxi Kangbao Intravenous Biological Products Factor VIII (plasma-Biological therapeutic; Blood constituents; derived), Beijing TiantanParenteral formulation unspecified Biological Products FLT-180aBiological therapeutic; Infusion; Vims recombinant SPK-8011 Biologicaltherapeutic; Infusion; Intravenous; WO-2018017956 Nanoparticleformulation injectable; Virus recombinant Fitusiran Biologicaltherapeutic; Oligonucleotide; WO-2004015107 Subcutaneous ValoctocogeneBiological therapeutic; Infusion; Intravenous; WO-2013186563roxaparvovec Virus recombinant AMT-061 Biological therapeutic; Infusion;Intravenous; WO-2009014445 Virus recombinant Fidanacogene Biologicaltherapeutic; Infusion; Intravenous; WO-02063025; elaparvovec Virusrecombinant WO-08400560; WO-09841240 Plasma-derived Factor Biologicaltherapeutic; Blood constituents; VIII, CSL/Zhong Yuan Parenteralformulation unspecified Rui De Biological Products SCT-800 Biologicaltherapeutic; Intravenous; Protein recombinant Moroctocog alfa/Chia TaiBiological therapeutic; Biosimilar product; Tianqing PharmaceuticalIntravenous; Peptide; Protein recombinant Group Factor IX/SichuanBiological therapeutic; Powder; Infusion; Yuanda Shuyang Intravenous;Peptide Pharmaceutical Factor VIII/Guangdong Biological therapeutic;Biosimilar product; Blood Danxia Biopharm constituents; IntravenousDalcinonacog Biological therapeutic; Intravenous; Protein WO-2012061654alfa/Catalyst Biosciences recombinant; Subcutaneous Marzeptacog alfaBiological therapeutic; Infusion; Intravenous; WO-2008127702;(activated) Protein recombinant; Subcutaneous; Sustained WO-2009126307release DTX-201 Biological therapeutic; Infusion; Intravenous; Virusrecombinant Factor IX gene therapy, Biological therapeutic; Intravenous;Virus WO-2010021692; Sangamo recombinant WO-2012051343 BIVV-001Biological therapeutic; Intravenous; Protein WO-2013122617 fusion;Protein recombinant; Subcutaneous SHP-654 Biological therapeutic;Infusion; Intravenous; WO-2018128688; Nanoparticle formulationinjectable; Protein WO-2018128689 recombinant; Virus recombinantMarstacimab Biological therapeutic; Immunoglobulin-G; WO-2017029583Infusion; Intravenous; Monoclonal antibody humanized; SubcutaneousSPK-8016 Biological therapeutic; Infusion; Intravenous; Virusrecombinant BAY-1093884 Biological therapeutic; Immunoglobulin-G;Intravenous; Monoclonal antibody human; Subcutaneous AAV2/8-HLP-FVIII-v3Biological therapeutic; Infusion; Intravenous; Virus recombinant SB-525Biological therapeutic; Gene transfer system non- WO-2015089046 viral;Infusion; Intravenous; Virus recombinant Concizumab Biologicaltherapeutic; Immunoglobulin-G; WO-2010072691 Monoclonal antibodyhumanized; Subcutaneous Factor VIIa-CTP Biological therapeutic;Intravenous; Protein WO-2011004361; fusion; Subcutaneous; Sustainedrelease WO-2013121416

Therapeutics for Hepatocellular Carcinoma

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a hepatocellular carcinoma drug.Hepatocellular carcinoma is the most common type of primary liver cancerand the most common cause of death in people with cirrhosis. Drugs totreat hepatocellular carcinoma include but are not limited to nivolumab,lenvatinib, sorafenib, regorafenib and carbozantinib.

Target-Based Therapeutics

GLP-1 Receptor Agonists

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a glucagon-like peptide 1 (GLP-1)receptor agonist. The GLP-1 pathway has been indicated in the treatmentof type 2 diabetes mellitus (T2DM). In some embodiments, the GLP-1receptor agonist is a peptide. In some embodiments, the GLP-1 receptoragonist is a small molecule. In some embodiments, the GLP-1 receptoragonist is formulated with a carrier, or delivery agent. In someembodiments, the carrier or delivery agent is a salt of a medium chainfatty acid derivative. In some embodiments, the carrier or deliveryagent is the sodium salt of N-[8-(2-hydroxybenzoyl)amino]caprylate(SNAC). In some embodiments, the carrier or delivery agent is biotin.

In some embodiments, the GLP-1 receptor agonist is exanatide (syntheticexendin-4), a 39-residue peptide which shares 53% sequence identity withGLP-1, having the sequence:

(SEQ ID NO: 1) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH₂.

In some embodiments, the GLP-1 receptor agonist is a compound with astructure selected from:

or any pharmaceutically acceptable salt thereof. In some embodiments,the GLP-1 receptor agonist is liraglutide (compound 3) or apharmaceutically acceptable salt thereof. In some embodiments, the GLP-1receptor agonist is semaglutide (compound 4) or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the GLP-1 receptor agonist is a compound having thestructure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GLP-1 receptor agonist is an 11-mer GLP-1receptor agonist. Exemplary 11-mer GLP-1 receptor agonists arerepresented by the structures and the table below.

hGLP-1R cAMP Cpd R¹ R² R³ R⁴ R⁵ R⁶ EC₅₀ (nM)  8 H Me H Bn BIP BIP 545  9H Me H Bn BIP(2′-Et,4′-OMe) BIP(2′-Me) 7.0 10 Me Me Me 2-F-BnBIP(2′-Et,4′-OMe) BIP(2′-Me) 0.087

In some embodiments, the GLP-1 receptor agonist is a compound having thestructure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GLP-1 receptor agonist is a compound with astructure selected from:

or a pharmaceutically acceptable salt thereof. In some embodiments, theGLP-1 receptor agonist is Boc5 (compound 12) or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the GLP-1 receptor agonist is a compound with astructure selected from:

or pharmaceutically acceptable salts thereof. In some embodiments, theGLP-1 receptor agonist is TTP-054 or a pharmaceutically acceptable saltthereof, such as described in Edmonds et al., Annu. Rep. Med. Chem.(2013) 48:119-130), which is herein incorporated by reference in itsentirety.

In some embodiments, the GLP-1 receptor agonist is OWL883, such asdescribed in Kawai et al., Diabetes (2018) 67(Supplement 1):1118-P,which is herein incorporated by reference in its entirety.

In some embodiments, the GLP-1 receptor agonist is a compound describedin Edmonds and Price, “Chapter Nine: Oral GLP-1 Modulators for theTreatment of Diabetes,” Ann. Rep. Med. Chem. (2013) 48:119-130, which isherein incorporated by reference in its entirety.

Other exemplary GLP-1 receptor agonists for delivery using any of thedevices or methods described herein include those listed in Table 9.

TABLE 9 GLP-1 receptor agonists adaptable for delivery via ingestibledevice for the treatment of the listed diseases and conditions GLP-1Agonist Dosage and (Company) Tradename Administration CommentsAlbiglutide Tanzeum 30 mg/dose (0.82 μmol); up to 50 GLP-1 (7-36) dimerfused to (GSK) EU: Eperzan mg/dose; Once weekly, recombinant humanalbumin. subcutaneus injection MWt ~73 kDa. Dulaglutide Trulicity 0.75mg/dose (0.024 μmol); up to GLP-1 (7-37) covalently (Eli Lilly) 1.5mg/dose; Once weekly, linked to an Fc fragment of subcutaneus injectionhuman IgG4. MWt ~63 kDa Exenatide Byetta 5 μg/dose (1.2 nmol); up to 10Synthetic form of exendin-4, (Astra μg/dose; Twice daily, subcutaneus apeptide isolated from H. Zeneca) injection suspectum venom MWt ~4 KDaBydureon, 2 mg/dose (0.48 μmole), Once Extended release microsphereBydureon weekly, subcutaneus injection formulations. Bcise LiraglutideVictoza 0.6 mg/dose (0.16 μmol); up to Fatty acylated GLP-1 analog.(Novo 1.8 mg/dose; Once daily, MWt ~4 KDa. Nordisk) subcutaneusinjection Saxenda 0.6 mg/dose (0.16 μmol); up to 3 mg/dose; Once daily,subcutaneus injection Lixisenatide Adlyxin 10 μg/dose (2.06 nmol); up to20 Recombinant DNA-produced (Sanofi- EU: Lyxumia μg/dose; Once daily,subcutaneus GLP-1 analog. Aventis) injection MWt ~5 KDa. SemaglutideOzempic 0.25 mg/dose (0.061 μmol); up to GLP-1-like peptide-1 analog.(Novo 1 mg/dose; Once weekly, MWt ~4 KDa. Nordisk) subcutaneus injectionLonger acting alternative to liraglutide.

PCSK9 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a proprotein convertase subtilisin/kexintype 9 (PCSK9) inhibitor. In some embodiments, the PCSK9 inhibitortreats one or more of endocrine and/or metabolic diseases or conditions,cardiovascular diseases, and infection. In some embodiments, theendocrine and/or metabolic disease or condition is familialhypercholesterolemia, hypercholesterolemia, or hyperlipidemia.

In some embodiments, the PCSK9 inhibitor is alirocumab. In someembodiments, the PCSK9 inhibitor is evolocumab. Other exemplary PCSK9inhibitors for delivery using any of the devices or methods describedherein include those listed in Table 10.

TABLE 10 PCSK9 inhibitors adaptable for delivery via ingestible devicefor the treatment of the listed diseases and conditions ExistingFormulation Technologies and Methods of Exemplary Patent Drug NameAdministration Therapy Area Active Indications Literature & Otheralirocumab Biological Endocrine/Metabolic; Atherosclerosis; WO2010077854therapeutic; Cell Cardiovascular; Familial Tavori, Hagai, cultureInfection hypercholesterolemia; Michelle Melone, technique;Hypercholesterolemia; and Shirya Rashid. Immunoglobulin- Lipidmetabolism “Alirocumab: G; Monoclonal disorder; Sepsis; PCSK9 inhibitorfor antibody Septic shock LDL cholesterol human; reduction.” ExpertSolution; review of Subcutaneous cardiovascular formulation therapy12.10 (2014): 1137-1144. evolocumab Biological Endocrine/MetabolicFamilial WO2009026558 therapeutic; Cell hypercholesterolemia;Kasichayanula, culture Hypercholesterolemia; Sreeneeranj, et al.technique; Hyperlipidemia; “Clinical Immunoglobulin- Lipid metabolismpharmacokinetics G; Monoclonal disorder and antibody pharmacodynamicshuman; of evolocumab, a Solution; PCSK9 inhibitor.” SubcutaneousClinical formulation pharmacokinetics 57.7 (2018): 769-779. bococizumabBiological Endocrine/Metabolic Hypercholesterolemia; Ridker, Paul M., ettherapeutic; Hyperlipidemia al. “Cardio vascular Humanized efficacy andsafety monoclonal of bococizumab in antibody high-risk patients.” NewEngland Journal of Medicine 376.16 (2017): 1527-1539. frovocimabBiological Endocrine/Metabolic Hypercholesterolemia; Kastelein, John JP,et therapeutic; Hyperlipidemia al. “Safety and humanized efficacy ofimmunoglobulin LY3015014, a G4 (IgG4) monoclonal antibody monoclonal toproprotein antibody convertase subtilisin/kexin type 9 (PCSK9): arandomized, placebo-controlled Phase 2 study.” European heart journal37.17 (2016): 1360-1369. 1D05-IgG2 Biological Endocrine/MetabolicHypercholesterolemia; Ni, Yan G., et al. “A therapeutic; HyperlipidemiaPCSK9-binding fully humanized antibody that monoclonal structurallymimics antibody the EGF (A) domain of LDL-receptor reduces LDLcholesterol in vivo.” Journal of lipid research 52.1 (2011): 78-86.evinacumab Biological Endocrine/Metabolic Hypercholesterolemia; U.S.Pat. No. 9,018,356 therapeutic; a Hyperlipidemia Gaudet, Daniel, etfully human al. “Safety and monoclonal efficacy of antibody toevinacumab, a ANGPTL3 monoclonal antibody to ANGPTL3, in patients withhomozygous familial hypercholesterolemia: A single-arm, open-label,proof-of- concept study.” Atherosclerosis 263 (2017): e9. LodelcizumabBiological Endocrine/Me tabolic; Cardiovascular; Hypercholesterolemia;WO2011072263 therapeutic; Infection Lipid metabolism monoclonaldisorder; Sepsis; antibody Septic shock SHR-1209 Antibody;Endocrine/Metabolic Hypercholesterolemia; WO2017114230 BiologicalHyperlipidemia therapeutic; Freeze drying; Subcutaneous formulationIBI-306 Biological Endocrine/Metabolic Hypercholesterolemia;WO2018113781 therapeutic; Hyperlipidemia Intravenous formulation;Monoclonal antibody human; Protein recombinant; Subcutaneous formulationLIB-003 Biological Endocrine/Metabolic Familial WO2011130354therapeutic; hypercholesterolemia; Infusion; HypercholesterolemiaIntravenous formulation; Protein fusion; Protein recombinant;Subcutaneous formulation JS-002 Biological Endocrine/MetabolicHypercholesterolemia; WO2017088782 therapeutic; Lipid metabolismInfusion; disorder Intravenous formulation; Monoclonal antibodyhumanized; Protein recombinant; Subcutaneous formulation AK-102Biological Endocrine/Metabolic Familial WO2016127912 therapeutic;hypercholesterolemia Humanized antibody; Subcutaneous formulation ATH-06Biological Cardiovascular; Hypercholesterolemia WO2015128287therapeutic: Endocrine/Me tabolic Peptide; Subcutaneous formulationATH-04 Biological Cardiovascular; Hypercholesterolemia WO2015128287therapeutic; Endocrine/Metabolic Peptide; Subcutaneous formulationC-8304 Oral Endocrine/Metabolic Hyperlipidemia WO2010075469 formulation;Small molecule therapeutic; Tablet formulation

TNFα Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a TNFα inhibitor. The terms “TNFαinhibitor” or “TNF-alpha inhibitor” refer to an agent which directly orindirectly inhibits, impairs, reduces, down-regulates, or blocks TNFαactivity and/or expression. In some embodiments, a TNFα inhibitor is aninhibitory nucleic acid, an antibody or an antigen-binding fragmentthereof, a fusion protein, a soluble TNFα receptor (a soluble TNFR1 or asoluble TNFR2), or a small molecule TNFα antagonist. In someembodiments, the inhibitory nucleic acid is a ribozyme, small hairpinRNA, a small interfering RNA, an antisense nucleic acid, or an aptamer.

In other examples, such indirect TNFα inhibitors can be a small moleculeinhibitor of a signaling component downstream of a TNFα receptor (e.g.,any of the signaling components downstream of a TNFα receptor describedherein or known in the art), a small molecule inhibitor of a proteinencoded by a TNFα-induced gene (e.g., any protein encoded by aTNFα-induced gene known in the art), and a small molecule inhibitor of atranscription factor selected from the group of NF-κB, c-Jun, and ATF2.

Inhibitory Nucleic Acids of TNFα

Exemplary TNFα inhibitors that are inhibitory nucleic acids targetingTNFα include, e.g., antisense DNA (e.g., Myers et al., J Pharmacol ExpTher. 304(1):411-424, 2003; Wasmuth et al., Invest. Opthalmol. Vis. Sci,2003; Dong et al., J. Orthop. Res. 26(8):1114-1120, 2008; U.S. PatentApplication Serial Nos. 2003/0083275, 2003/0022848, and 2004/0770970;ISIS 104838; U.S. Pat. Nos. 6,180,403, 6,080,580, and 6,228,642; Kobziket al., Inhibition of TNF Synthesis by Antisense Oligonucleotides, inManual of Antisense Methodology, Kluwer Academic Publishers, Vol. 4, pp.107-123, 1999; Taylor et al., Antisense Nucleic Acid Drug Develop.8(3):199-205, 1998; Mayne et al., Stroke 32:240-248, 2001; Mochizuki etal., J. Controlled Release 151(2):155-161, 2011; Dong et al., J.Orthopaedic Res. 26(8):1114-1120, 2008; Dong et al., Pharm. Res.28(6):1349-1356, 2011; and Pampfer et al., Biol. Reproduction52(6):1316-1326, 1995), antisense RNA, short interfering RNA (siRNA)(e.g., Taishi et al., Brain Research 1156:125-132, 2007; Presumey etal., Eur. J. Pharm. Biopharm. 82(3):457-467, 2012; Laroui et al., J.Controlled Release 186:41-53, 2014; D'Amore et al., Int. J.Immunopathology Pharmacol. 21:1045-1047, 2008; Choi et al., J. Dermatol.Sci. 52:87-97, 2008; Qin et al., Artificial Organs 35:706-714, 2011;McCarthy et al., J. Controlled Release 168: 28-34, 2013; Khoury et al.,Current Opin. Mol. Therapeutics 9(5):483-489, 2007; Lu et al., RNAInterference Technology From Basic Science to Drug Development 303,2005; Xie et al., PharmaGenomics 4(6):28-34, 2004; Aldawsari et al.,Current Pharmaceutical Design 21(31):4594-4605, 2015; Zheng et al.,Arch. Med. Sci. 11:1296-1302, 2015; Peng et al., Chinese J. Surgery47(5):377-380, 2009; Aldayel et al., Molecular Therapy. Nucleic Acids5(7):e340, 2016; Bai et al., Current Drug Targets 16:1531-1539, 2015;U.S. Patent Application Publications Nos. 2008/0097091, 2009/0306356,and 2005/0227935; and WO 14/168264), short hairpin RNA (shRNA) (e.g.,Jakobsen et al., Mol. Ther. 17(10): 1743-1753, 2009; Ogawa et al., PLoSOne 9(3): e92073, 2014; Ding et al., Bone Joint 94-6(Suppl. 11):44,2014; and Hernandez-Alejandro et al., J. Surgical Res. 176(2):614-620,2012), and microRNAs (see, e.g., WO 15/26249). In some embodiments, theinhibitory nucleic acid blocks pre-mRNA splicing of TNFα (e.g., Chiu etal., Mol. Pharmacol. 71(6): 1640-1645, 2007).

In some embodiments, the inhibitory nucleic acid, e.g., an aptamer(e.g., Orava et al., ACS Chem Biol. 2013; 8(1): 170-178, 2013), canblock the binding of a TNFα protein with its receptor (TNFR1 and/orTNFR2).

In some embodiments, the inhibitory nucleic acid can down-regulate theexpression of a TNFα-induced downstream mediator (e.g., TRADD, TRAF2,MEKK1/4, MEKK4/7, JNK, AP-1, ASK1, RIP, MEKK 3/6, MAPK, NIK, IKK, NF-κB,p38, JNK, IκB-α, or CCL2). Further teachings of downstream TNFα-inducedmediators can be found in, e.g., Schwamborn et al., BMC Genomics 4:46,2003; and Zhou et al., Oncogene 22: 2034-2044, 2003, incorporated byreference herein. Additional aspects of inhibitory nucleic acids aredescribed in Aagaard et al., Adv. Drug Delivery Rev. 59(2):75-86, 2007,and Burnett et al., Biotechnol. J. 6(9):1130-1146, 2011.

TNFα Inhibitor Antibodies

In some embodiments, the TNFα inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment described hereinbinds specifically to any one of TNFα, TNFR1, or TNFR2. In someembodiments, an antibody or antigen-binding fragment of an antibodydescribed herein can bind specifically to TNFα. In some embodiments, anantibody or antigen-binding fragment of an antibody described herein canbind specifically to an TNFα receptor (TNFR1 or TNFR2).

Non-limiting examples of TNF inhibitors that are antibodies thatspecifically bind to TNFα are described in Elliott et al., Lancet 1994;344: 1125-1127, 1994; Rankin et al., Br. J. Rheumatol. 2:334-342, 1995;Butler et al., Eur. Cytokine Network 6(4):225-230, 1994; Lorenz et al.,J. Immunol. 156(4):1646-1653, 1996; Hinshaw et al., Circulatory Shock30(3):279-292, 1990; Wanner et al., Shock 11(6):391-395, 1999; Bongartzet al., JAMA 295(19):2275-2285, 2006; Knight et al., Molecular Immunol.30(16):1443-1453, 1993; Feldman, Nature Reviews Immunol. 2(5):364-371,2002; Taylor et al., Nature Reviews Rheumatol. 5(10):578-582, 2009;Garces et al., Annals Rheumatic Dis. 72(12):1947-1955, 2013; Palladinoet al., Nature Rev. Drug Discovery 2(9):736-746, 2003; Sandborn et al.,Inflammatory Bowel Diseases 5(2):119-133, 1999; Atzeni et al.,Autoimmunity Reviews 12(7):703-708, 2013; Maini et al., Immunol. Rev.144(1):195-223, 1995; Ordas et al., Clin. Pharmacol. Therapeutics91(4):635-646, 2012; Cohen et al., Canadian J. Gastroenterol. Hepatol.15(6):376-384, 2001; Feldmann et al., Ann. Rev. Immunol. 19(1):163-196,2001; Ben-Horin et al., Autoimmunity Rev. 13(1):24-30, 2014; and U.S.Pat. Nos. 6,090,382; 6,258,562; and 6,509,015).

In certain embodiments, the TNFα inhibitor can include or is infliximab(Remicade™), CDP571, CDP 870, golimumab (Golimumab™), adalimumab(Humira™) or certolizumab pegol (Cimzia™). In certain embodiments, theTNFα inhibitor can be a TNFα inhibitor biosimilar. Examples of approvedand late-phase TNFα inhibitor biosimilars include, but are not limitedto, infliximab biosimilars such as Remsima™ and Inflectra® (CT-P13) fromCelltrion/Pfizer, GS071 from Aprogen, Flixabi™ (SB2) from SamsungBioepis, PF-06438179 from Pfizer/Sandoz, NI-071 from Nichi-IkoPharmaceutical Co., and ABP 710 from Amgen; adalimumab biosimilars suchas Exemptia™ (ZRC3197) from Zydus Cadila, India, Solymbic® and Amgevita®(ABP 501) from Amgen, Imraldi (SB5) from Samsung Bioepis, GP-2017 fromSandoz, Switzerland, ONS-3010 from Oncobiologics/Viropro, U.S.A., M923from Momenta Pharmaceuticals/Baxalta (Baxter spinoff USA), PF-06410293from Pfizer, BMO-2 or MYL-1401-A from Biocon/Mylan, CHS-1420 fromCoherus, FKB327 from Fujifilm/Kyowa Hakko Kirin (Fujifilm Kyowa KirinBiologics), Cyltezo (BI 695501) from Boehringer Ingelheim, CT-P17 fromCelltrion, BAX 923 from Baxalta (now a part of Shire), MSB11022 fromFresenius Kabi (bought from Merck kGaA (Merck Group) in 2017), LBAL fromLG Life Sciences/Mochida Pharmaceutical, South Korea/Japan, PBP1502 fromPrestige Biopharma, Adfrar from Torrent Pharmaceuticals, India, abiosimilar of adalimumab in development by Adello Biologics, abiosimilar of adalimumab in development by AET Biotech/BioXpressTherapeutics, Germany/Switzerland, a biosimilar of adalimumab frommAbxience, Spain, a biosimilar of adalimumab in development byPlantForm, Canada; and etanercept biosimilars such as Erelzi™ fromSandoz/Novartis, Brenzys™ (SB4) from Samsung Bioepis, GP2015 fromSandoz, TuNEX® from Mycenax, LBEC0101 from LG Life, and CHS-0214 fromCoherus.

In some embodiments, the TNFα inhibitor can be SAR252067 (e.g., amonoclonal antibody that specifically binds to TNFSF14, described inU.S. Patent Application Publication No. 2013/0315913) or MDGN-002(described in U.S. Patent Application Publication No. 2015/0337046). Insome embodiments, the TNFα inhibitor can be PF-06480605, which bindsspecifically to TNF SF15 (e.g., described in U.S. Patent ApplicationPublication No. 2015/0132311). Additional examples of TNFα inhibitorsinclude DLCX105 (described in Tsianakas et al., Exp. Dermatol.25:428-433, 2016) and PF-06480605, which binds specifically to TNFSF15(described in U.S. Patent Application Publication No. 2015/0132311).Further examples of TNFα inhibitors that are antibodies orantigen-binding antibody fragments are described in, e.g., WO 17/158097,EP 3219727, WO 16/156465, and WO 17/167997.

In some embodiments, the TNFα inhibitor is DLX-105, e.g., the gelformulation.

In some embodiments, the TNFα inhibitor is adalimumab. Adalimumab is arecombinant human IgG1 monoclonal antibody specific for human tumornecrosis factor and is indicated for the treatment of variousinflammatory diseases such as rheumatoid arthritis, Crohn's disease, andulcerative colitis.

Adalimumab is currently delivered as an SC injection of 40 mg in 0.4-0.8mL once every 1-2 weeks. It is sold in prefilled pen injectors forself-administration. The bioavailability is approximately 64% by SCinjection, the half-life is approximately 2 weeks, and intracellularcatabolism is the primary mode of elimination. Adalimumab must berefrigerated but can be temporarily stored at room temperature beforeuse.

Adalimumab is a suitable therapeutic for delivery via ingestible deviceas described herein. It is currently available as a liquid, administeredby self-injection, and, because adverse injection site reactions are notuncommon, patients may readily adopt an alternative dosage form. Lastly,the probability of acute reactions to overdose is low which,theoretically, could allow an increase in dose to compensate for lowerbioavailability than SC injection.

TNFα Inhibitor Fusion Proteins

In some embodiments, the TNFα inhibitory agent is a fusion protein(e.g., an extracellular domain of a TNFR fused to a partner peptide,e.g., an Fc region of an immunoglobulin, e.g., human IgG) (see, e.g.,Peppel et al., J. Exp. Med. 174(6):1483-1489, 1991; Deeg et al.,Leukemia 16(2):162, 2002) or a soluble TNFR (e.g., TNFR1 or TNFR2) thatbinds specifically to TNFα. In some embodiments, the TNFα inhibitorincludes or is etanercept (Enbrel™) (see, e.g., WO 91/03553 and WO09/406,476, incorporated by reference herein). In some embodiments, theTNFα inhibitor includes or is r-TBP-I (e.g., Gradstein et al., J.Acquir. Immune Defic. Syndr. 26(2): 111-117, 2001). In some embodiments,the TNFα inhibitor includes or is a soluble TNFα receptor (e.g., Watt etal., J Leukoc Biol. 66(6):1005-1013, 1999; Tsao et al., Eur Respir J.14(3):490-495, 1999; Kozak et al., Am. J. Physiol. Reg. IntegrativeComparative Physiol. 269(1):R23-R29, 1995; Mohler et al., J. Immunol.151(3):1548-1561, 1993; Nophar et al., EMBO J. 9(10):3269, 1990;Bjornberg et al., Lymphokine Cytokine Res. 13(3):203-211, 1994; Piguetet al., Eur. Respiratory J. 7(3):515-518, 1994; and Gray et al., Proc.Natl. Acad. Sci. U.S.A. 87(19):7380-7384, 1990).

In some embodiments, the TNFα inhibitor is tulinercept.

TNFα Inhibitor Small Molecules

In some embodiments, the TNFα inhibitor is a small molecule. In someembodiments, the TNFα inhibitor is C87 (Ma et al., J. Biol. Chem.289(18):12457-66, 2014). In some embodiments, the small molecule isLMP-420 (e.g., Haraguchi et al., AIDS Res. Ther. 3:8, 2006). In someembodiments, the small molecule is a tumor necrosis factor-convertingenzyme (TACE) inhibitor (e.g., Moss et al., Nature Clinical PracticeRheumatology 4: 300-309, 2008). In some embodiments, the TACE inhibitoris TMI-005 and BMS-561392. Additional examples of small moleculeinhibitors are described in, e.g., He et al., Science310(5750):1022-1025, 2005.

In some examples, the TNFα inhibitor is a small molecule that inhibitsthe activity of one of TRADD, TRAF2, MEKK1/4, MEKK4/7, JNK, AP-1, ASK1,RIP, MEKK 3/6, MAPK, NIK, IKK, and NF-κB, in a mammalian cell.

In some examples, the TNFα inhibitor is a small molecule that inhibitsthe activity of one of CD14, MyD88 (see, e.g., Olson et al., ScientificReports 5:14246, 2015), IRAK (Chaudhary et al., J. Med. Chem.58(1):96-110, 2015), lipopolysaccharide binding protein (LBP) (see,e.g., U.S. Pat. No. 5,705,398), TRAF6 (e.g.,3-[(2,5-Dimethylphenyl)amino]-1-phenyl-2-propen-1-one), ras (e.g., Bakeret al., Nature 497:577-578, 2013), raf (e.g., vemurafenib (PLX4032,RG7204), sorafenib tosylate, PLX-4720, dabrafenib (GSK2118436),GDC-0879, RAF265 (CHIR-265), AZ 628, NVP-BHG712, SB590885, ZM 336372,sorafenib, GW5074, TAK-632, CEP-32496, encorafenib (LGX818), CCT196969,LY3009120, R05126766 (CH5126766), PLX7904, and MLN2480), MEK1/2 (e.g.,Facciorusso et al., Expert Review Gastroentrol. Hepatol. 9:993-1003,2015), ERK1/2 (e.g., Mandal et al., Oncogene 35:2547-2561, 2016), NIK(e.g., Mortier et al., Bioorg. Med. Chem. Lett. 20:4515-4520, 2010), IKK(e.g., Reilly et al., Nature Med. 19:313-321, 2013), IκB (e.g., Suzukiet al., Expert. Opin. Invest. Drugs 20:395-405, 2011), NF-κB (e.g.,Gupta et al., Biochim. Biophys. Acta 1799(10-12):775-787, 2010), rac(e.g., U.S. Pat. No. 9,278,956), MEK4/7, JNK (e.g., AEG 3482, BI 78D3,CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, andTCS JNK6o), c-jun (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), MEK3/6 (e.g.,Akinleye et al., J. Hematol. Oncol. 6:27, 2013), p38 (e.g., AL 8697, AMG548, BIRB 796, CMPD-1, DBM 1285 dihydrochloride, EO 1428, JX 401, ML3403, Org 48762-0, PH 797804, RWJ 67657, SB 202190, SB 203580, SB239063, SB 706504, SCIO 469, SKF 86002, SX 011, TA 01, TA 02, TAK 715,VX 702, and VX 745), PKR (e.g., 2-aminopurine or CAS 608512-97-6), TTP(e.g., CAS 329907-28-0), and MK2 (PF 3644022 and PHA 767491).

IL-1 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is an IL-1 inhibitor. The term “IL-1inhibitor” refers to an agent that decreases the expression of an IL-1cytokine or an IL-1 receptor and/or decreases the ability of an IL-1cytokine to bind specifically to an IL-1 receptor. Non-limiting examplesof IL-1 cytokines include IL-1α, IL-1β, IL-18, IL-36a, IL-36β, IL-36γ,IL-38, and IL-33. In some examples, an IL-1 cytokine is IL-1α. In someexamples, an IL-1 cytokine is IL-1β.

In some embodiments, an IL-1 inhibitory agent is an inhibitory nucleicacid, an antibody or fragment thereof, or a fusion protein. In someembodiments, the inhibitory nucleic acid is an antisense nucleic acid, aribozyme, or a small interfering RNA.

Inhibitory Nucleic Acids of IL-1

Inhibitory nucleic acids that can decrease the expression of IL-1α,IL-1β, IL-18, IL-36α, IL-36β, IL-36γ, IL-38, IL-33, IL-1R1, IL1RAP,IL-18Rα, IL-1RL2, or IL1RL1 mRNA expression in a mammalian cell includeantisense nucleic acid molecules, i.e., nucleic acid molecules whosenucleotide sequence is complementary to all or part of an IL-1α, IL-1β,IL-18, IL-36α, IL-36β, IL-36γ, IL-38, IL-33, IL-1R1, IL1RAP, IL-18Rα,IL-1RL2, or IL1RL1 mRNA (e.g., complementary to all or a part of any oneof SEQ ID NOs: 85-125).

Examples of modified nucleotides which can be used to generate anantisense nucleic acid include 5-fluorouracil, 5-bromouracil,5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine,5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can beproduced biologically using an expression vector into which a nucleicacid has been subcloned in an antisense orientation (i.e., RNAtranscribed from the inserted nucleic acid will be of an antisenseorientation to a target nucleic acid of interest).

Inhibitory nucleic acids preferentially bind (e.g., hybridize) to anucleic acid encoding IL-1α, IL-1β, IL-18, IL-36α, IL-36β, IL-36γ,IL-38, IL-33, IL-1R1, IL1RAP, IL-18Rα, IL-1RL2, or IL1RL1 protein totreat allergic diseases (e.g., asthma (Corren et al., N. Engl. J. Med.365: 1088-1098, 2011)), radiation lung injury (Chung et al., Sci. Rep.6: 39714, 2016), ulcerative colitis (Hua et al., Br. J. Clin. Pharmacol.80:101-109, 2015), dermatitis (Guttman-Yassky et al., Exp. Opin. Biol.Ther. 13(4):1517, 2013), and chronic obstructive pulmonary disease(COPD) (Walsh et al. (2010) Curr. Opin. Investig Drugs.11(11):1305-1312, 2010).

Exemplary IL-1 inhibitors that are antisense nucleic acids are describedin Yilmaz-Elis et al., Mol. Ther. Nucleic Acids 2(1): e66, 2013; Lu etal., J. Immunol. 190(12): 6570-6578, 2013), small interfering RNA(siRNA) (e.g., Ma et al., Ann. Hepatol. 15(2): 260-270, 2016), orcombinations thereof. In certain embodiments, a therapeuticallyeffective amount of an inhibitory nucleic acid targeting a nucleic acidencoding IL-1α, IL-1β, IL-18, IL-36α, IL-36β, IL-36γ, IL-38, IL-33,IL-1R1, IL1RAP, IL-18Rα, IL-1RL2, or IL1RL1 protein can be administeredto a subject (e.g., a human subject) in need thereof.

IL-1 Inhibitor Antibodies

In some embodiments, the IL-1 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, the IL-1 inhibitor is canakinumab (ACZ885, Ilaris®(Dhimolea, MAbs 2(1): 3-13, 2010; Yokota et al., Clin. Exp. Rheumatol.2016; Torene et al., Ann. Rheum. Dis. 76(1):303-309, 2017; Gram, Curr.Opin. Chem. Biol. 32:1-9, 2016; Kontzias et al., Semin. Arthritis Rheum42(2):201-205, 2012). In some embodiments, the IL-1 inhibitor isanakinra (Kineret®; Beynon et al., J. Clin. Rheumatol. 23 (3): 181-183,2017; Stanam et al., Oncotarget 7(46):76087-76100, 2016; Nayki et al.,J. Obstet Gynaecol. Res. 42(11):1525-1533, 2016; Greenhalgh et al., Dis.Model Mech. 5(6):823-833, 2012), or a variant thereof. In someembodiments, the IL-1 inhibitor is gevokizumab (XOMA 052; Knicklebein etal., Am. J. Ophthalmol. 172:104-110, 2016; Roubille et al.,Atherosclerosis 236(2):277-285, 2014; Issafras et al., J. Pharmacol.Exp. Ther 348(1):202-215, 2014; Handa et al., Obesity 21(2):306-309,2013; Geiler et al., Curr. Opin. Mol. Ther. 12(6):755-769, 2010),LY2189102 (Bihorel et al., AAPS J. 16(5):1009-1117, 2014;Sloan-Lancaster et al., Diabetes Care 36(8):2239-2246, 2013), MABp1(Hickish et al., Lancey Oncol. 18(2):192-201, 2017; Timper et al., J.Diabetes Complications 29(7):955-960, 2015), CDP-484 (Braddock et al.,Drug Discov. 3:330-339, 2004), or a variant thereof (Dinarello et al.,Nat. Rev. Drug Discov. 11(8): 633-652, 2012).

Further teachings of IL-1 inhibitors that are antibodies orantigen-binding fragments thereof are described in U.S. Pat. Nos.5,075,222; 7,446,175; 7,531,166; 7,744,865; 7,829,093; and 8,273,350; US2016/0326243; US 2016/0194392, and US 2009/0191187, each of which isincorporated by reference in its entirety.

IL-1 Inhibitor Fusion Proteins or Soluble Receptors

In some embodiments, the IL-1 inhibitor is a fusion protein or a solublereceptor. For example, a fusion can include an extracellular domain ofany one of IL-1R1, IL1RAP, IL-18Rα, IL-1RL2, and IL1RL1 fused to apartner amino acid sequence (e.g., a stabilizing domain, e.g., an IgG Fcregion, e.g., a human IgG Fc region). In some embodiments, the IL-1inhibitor is a soluble version of one or both of IL-1RL1 and IL1RAP. Insome embodiments, the IL-1 inhibitor is a soluble version of IL-18Rα. Insome embodiments, the IL-1 inhibitor is a soluble version of one or bothof IL-1RL2 and IL-1RAP.

In some embodiments, the IL-1 inhibitor is a fusion protein comprisingor consisting of rilonacept (IL-1 Trap, Arcalyst®) (see, e.g., Kapur &Bonk, P.T. 34(3):138-141, 2009; Church et al., Biologics 2(4):733-742,2008; McDermott, Drugs Today (Banc) 45(6):423-430, 2009). In someembodiments, the IL-1 inhibitor is a fusion protein that is chimeric(e.g., EBI-005 (Isunakinra®) (Furfine et al., Invest. Ophthalmol. Vis.Sci. 53(14):2340-2340, 2012; Goldstein et al., Eye Contact Lens41(3):145-155, 2015; Goldstein et al., Eye Contact Lens, 2016)).

In some embodiments, the IL-1 inhibitor is a soluble receptor thatcomprises or consists of sIL-1RI and/or sIL-1RII (Svenson et al., Eur.J. Immunol. 25(10): 2842-2850, 1995).

IL-1 Inhibitor Endogenous Peptides

In some embodiments, the IL-1 inhibitor can be an endogenous ligand oran active fragment thereof, e.g., IL-1Ra or IL-36Ra. IL-1Ra is anendogenous soluble protein that decreases the ability of IL-1α and IL-1βto bind to their receptor (e.g., a complex of IL-1R1 and IL1RAPproteins). IL-36Ra is an endogenous soluble protein that decreases theability of IL-36α, IL-36β, and IL-36γ to bind to their receptor (e.g., acomplex of IL-1RL2 and IL-1RAP proteins). Exemplary sequences for IL-1Raand IL-36Ra are shown below.

In some embodiments, the IL-1 inhibitor is K(D)PT.

IL-6 Receptor Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is an IL-6 receptor inhibitor. The term“IL-6 receptor inhibitor” refers to an agent which decreases IL-6receptor expression and/or the ability of IL-6 to bind to an IL-6receptor. In some embodiments, the IL-6 receptor inhibitor targets theIL-6 receptor β-subunit, glycoprotein 130 (sIL6gp130). In otherembodiments, the IL-6 receptor inhibitor targets the IL-6 receptorsubunit (IL6R). In other embodiments, the IL-6 receptor inhibitortargets the complex consisting of both the IL-6 receptor subunit (IL6R)and the IL-6 receptor β-subunit, glycoprotein 130 (sIL6gp130). In someembodiments, the IL-6 receptor inhibitor targets IL-6.

In some embodiments, an IL-6 receptor inhibitor is an inhibitory nucleicacid, an antibody or an antigen-binding fragment thereof, a fusionprotein, a IL-6 receptor antagonist, or a small molecule. In someembodiments, the inhibitory nucleic acid is a small interfering RNA, anantisense nucleic acid, an aptamer, or a microRNA. Exemplary IL-6receptor inhibitors are described herein. Additional examples of IL-6receptor inhibitors are known in the art.

Inhibitory Nucleic Acids of IL-6

An antisense nucleic acid molecule can be complementary to all or partof a non-coding region of the coding strand of a nucleotide sequenceencoding an IL6R, sIL6gp130, or IL-6 protein. Non-coding regions (5′ and3′ untranslated regions) are the 5′ and 3′ sequences that flank thecoding region in a gene and are not translated into amino acids.

Exemplary antisense nucleic acids that are IL-6 receptor inhibitors aredescribed in Keller et al., J. Immunol. 154(8):4091-4098, 1995; andJiang et al., Anticancer Res. 31(9): 2899-2906, 2011.

Non-limiting examples of short interfering RNA (siRNA) that are IL-6receptor inhibitors are described in Yi et al., Int. J. Oncol.41(1):310-316, 2012; and Shinriki et al., Clin. Can. Res.15(17):5426-5434, 2009). Non-limiting examples of microRNAs that areIL-6 receptor inhibitors are described in miR34a (Li et al., Int. J.Clin. Exp. Pathol. 8(2):1364-1373, 2015) and miR-451 (Liu et al., CancerEpidemiol. 38(1):85-92, 2014).

Non-limiting examples of aptamers that are IL-6 receptor inhibitors aredescribed in Meyer et al., RNA Biol. 11(1):57-65, 2014; Meyer et al.,RNA Biol. 9(1):67-80, 2012; and Mittelberger et al., RNA Biol.12(9):1043-1053, 2015. Additional examples of inhibitory nucleic acidsthat are IL-6 receptor inhibitors are described in, e.g., WO 96/040157.

IL-6 Inhibitor Antibodies

In some embodiments, the IL-6 receptor inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment described hereinbinds specifically to IL-6. In some embodiments, an antibody orantigen-binding fragment described herein binds specifically to IL-6receptor (e.g., one or both of IL6R and sIL6gp130).

In certain embodiments, the antibody comprises or consists of anantigen-binding fragment or portion of tocilizumab (artlizumab,Actemra®; Sebba, Am. J. Health Syst. Pharm. 65(15):1413-1418, 2008;Tanaka et al., FEBS Letters 585(23):3699-3709, 2011; Nishimoto et al.,Arthritis Rheum. 50:1761-1769, 2004; Yokota et al., Lancet371(9617):998-1006, 2008; Emery et al., Ann. Rheum. Dis.67(11):1516-1523, 2008; Roll et al., Arthritis Rheum. 63(5):1255-1264,2011); lazakizumab (BMS945429; ALD518, a humanized monoclonal antibodythat binds circulating IL-6 cytokine rather than the IL-6 receptor,blocking both classic signaling and trans-signaling (Weinblatt, MichaelE., et al. “The Efficacy and Safety of Subcutaneous Clazakizumab inPatients With Moderate-to-Severe Rheumatoid Arthritis and an InadequateResponse to Methotrexate: Results From a Multinational, Phase IIb,Randomized, Double-Blind, Placebo/Active-Controlled, Dose-RangingStudy.” Arthritis & Rheumatology 67.10 (2015): 2591-2600)); sarilumab(REGN88 or SAR153191; Huizinga et al., Ann. Rheum. Dis. 73(9):1626-1634,2014; Sieper et al., Ann. Rheum. Dis. 74(6):1051-1057, 2014; Cooper,Immunotherapy 8(3): 249-250, 2016); MR-16 (Hartman et al., PLosOne11(12):e0167195, 2016; Fujita et al., Biochim. Biophys. Acta.10:3170-80, 2014; Okazaki et al., Immunol. Lett. 84(3):231-40, 2002;Noguchi-Sasaki et al., BMC Cancer 16:270, 2016; Ueda et al., Sci. Rep.3:1196, 2013); rhPM-1 (MRA; Nishimoto et al., Blood 95: 56-61, 2000;Nishimoto et al., Blood 106: 2627-2632, 2005; Nakahara et al., ArthritisRheum. 48(6): 1521-1529, 2003); NI-1201 (Lacroix et al., J. Biol. Chem.290(45):26943-26953, 2015); EBI-029 (Schmidt et al., ElevenBiotherapeutics Poster #B0200, 2014). In some embodiments, the antibodyis a nanobody (e.g., ALX-0061 (Van Roy et al., Arthritis Res. Ther. 17:135, 2015; Kim et al., Arch. Pharm. Res. 38(5):575-584, 2015)). In someembodiments, the antibody is NRI or a variant thereof (Adachi et al.,Mol. Ther. 11(1):5262-263, 2005; Hoshino et al., Can. Res. 67(3):871-875, 2007). In some embodiments, the antibody is PF-04236921(Pfizer) (Wallace et al., Ann. Rheum. Dis. 76(3):534-542, 2017).

In some embodiments, the IL-6 receptor inhibitor is olokizumab(CDP-6038).

IL-6 Inhibitor Fusion Proteins

In some embodiments, the IL-6 receptor inhibitor is a fusion protein, asoluble receptor, or a peptide (see e.g., U.S. Pat. No. 5,591,827). Insome embodiments, the IL-6 receptor fusion protein comprises or consistsof soluble gp130 (Jostock et al., Eur. J. Biochem. 268(1):160-167, 2001;Richards et al., Arthritis Rheum. 54(5):1662-1672, 2006; Rose-John etal., Exp. Opin. Ther. Targets 11(5):613-624, 2007).

In some embodiments, the IL-6 receptor fusion protein comprises orconsists of FE999301 (Jostock et al., Eur. J. Biochem. 268(1):160-167,2001) or sgp130Fc protein (Jones et al., J. Clin. Invest.121(9):3375-3383, 2011). In some embodiments, the IL-6 receptorinhibitor is a peptide (e.g., S7 (Su et al., Cancer Res.65(11):4827-4835, 2005). In some embodiments, the IL-6 receptorinhibitor is a triterpenoid saponin (e.g., chikusetsuaponin IVa butylester (CS-Iva-Be) (Yang et al., Mol. Cancer. Ther. 15(6):1190-200,2016).

IL-6 Inhibitor Small Molecules

In some embodiments, the IL-6 receptor inhibitor is a small molecule(see, e.g., U.S. Pat. No. 9,409,990). In some embodiments, the smallmolecule is LMT-28 (Hong et al., J. Immunol. 195(1): 237-245, 2015);ERBA (Enomoto et al., Biochem. Biophys. Res. Commun. 323:1096-1102,2004; Boos et al., J. Nat. Prod. 75(4):661-668, 2012), ERBF (TB-2-081)(Hayashi et al., J. Pharmacol. Exp. Ther. 303:104-109, 2002; Vardanyanet al., Pain 151(2):257-265, 2010; Kino et al., J. Allergy Clin.Immunol. 120(2):437-444, 2007), or a variant thereof.

In some embodiments, the IL-6 receptor inhibitor is YSIL6.

IL-10 Receptor Agonists

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is an IL-10 receptor agonist. The term“IL-10 receptor agonist” is any molecule that binds to and activates areceptor for IL-10 expressed on a mammalian cell or a nucleic acid thatencodes any such molecule. A receptor for IL-10 can include, e.g., acomplex of two IL-10 receptor-1 (IL-10R1) proteins and two IL-10receptor 2 (IL-10R2) proteins. In some examples, an IL-10 receptoragonist is an antibody or an antigen-binding antibody fragment thatspecifically binds to and activates a receptor for IL-10 (e.g., a humanreceptor for IL-10). In some examples, an IL-10 receptor agonist is arecombinant IL-10 (e.g., human recombinant IL-10). In some examples, anIL-10 receptor agonist is a pegylated recombinant IL-10 (e.g., pegylatedrecombinant human IL-10). In some examples, an IL-10 receptor agonist isa fusion protein. In some examples, an IL-10 receptor agonist is anIL-10 peptide mimetic.

Nucleic Acids and Vectors that Encode an IL-10 Receptor Agonist

In some examples, an IL-10 receptor agonist can be a nucleic acid (e.g.,a vector) that includes a sequence encoding an IL-10 receptor agonist(e.g., any of the IL-10 proteins described herein). A non-limitingexample of a composition including a nucleic acid that encodes an IL-10receptor agonist is XT-150 (Xalud Therapeutics).

IL-10 Inhibitor Antibodies and Antigen-Binding Fragments

In some embodiments, the IL-10 receptor agonist is an antibody or anantigen-binding antibody fragment that binds to and activates an IL-10receptor (e.g., a human IL-10 receptor). In some embodiments, theantibody or antigen-binding antibody fragment that specifically binds toan epitope on IL-10R-1 protein (e.g., human IL-10R-1 protein). In someembodiments, the antibody or antigen-binding antibody fragment thatspecifically binds to an epitope on IL-10R-2 protein (e.g., a humanIL-10R-2 protein). In some embodiments, the antibody or theantigen-binding antibody fragment that specifically binds to an epitopeon IL-10R-1 and IL-10R-2 proteins (e.g., human IL-10R-1 and humanIL-10R-2 proteins).

In some embodiments, the IL-10 receptor agonist is an antibody, e.g.,F8-IL10 (also known as DEKAVIL) or a variant thereof (see, e.g.,Schwager et al., Arthritis Res. Ther. 11(5):R142, 2009; Franz et al.,Int. J. Cardiol. 195:311-322, 2015; Galeazzi et al., Isr. Med. Assoc. J.16(10):666, 2014).

IL-10 Inhibitor Fusion Proteins

In some embodiments, the IL-10 receptor agonist is a fusion protein. Insome embodiments, the fusion protein comprises the amino acid sequenceof an IL-10 protein (or a functional fragment thereof) and a fusionpartner (e.g., an Fc region (e.g., human IgG Fc) or human serumalbumin). In some embodiments the fusion partner can be an antibody oran antigen-binding antibody fragment (e.g., an scFv) that targets IL-10receptor agonist to an inflamed tissue. In some embodiments, theantibody or antigen-binding fragment that is a fusion partner can bindspecifically, or preferentially, to inflamed gastrointestinal cells by,e.g., CD69. In some embodiments, an IL-10 receptor agonist that is afusion protein can be, e.g., F8-IL-10, such as Dekavil (Philogen).

In some embodiments, the fusion protein is a L19-IL-10 fusion protein, aHyHEL10-IL-10 fusion protein, or a variant thereof. See, e.g., Trachselet al., Arthritis Res. Ther. 9(1):R9, 2007, and Walmsley et al.,Arthritis Rheum. 39: 495-503, 1996.

In some embodiments, the IL-10 receptor agonist is RG-7880.

IL-10 Peptide Mimetic

In some embodiments, the IL-10 receptor agonist is an IL-10 peptidemimetic. A non-limiting example of an IL-10 peptide mimetic is IT 9302or a variant thereof (Osman et al., Surgery 124(3):584-92, 1998; Lopezet al., Immunobiology 216(10):1117-1126, 2011). Additional examples ofIL-10 peptide mimetics are described in DeWitt, Nature Biotech. 17:214,1999, and Reineke et al., Nature Biotech. 17:271-275, 1999.

Recombinant IL-10

In some examples, an IL-10 receptor agonist is a recombinant IL-10protein. In some examples, a recombinant human IL-10 protein can beTenovil (Schering Corporation). In some examples, a recombinant IL-10protein is a functional fragment of human IL-10 protein (e.g., SEQ IDNO: 140).

In some embodiments, the IL-10 receptor agonist is rhuIL-10 (Tenovil) ora variant thereof. See, e.g., McHutchison et al., J. Interferon CytokineRes. 1:1265-1270, 1999; Rosenblum et al., Regul. Toxicol. Pharmacol.35:56-71, 2002; Schreiber et al., Gastroenterology 119(6):1461-1472,2000; Maini et al., Arthritis Rheum. 40(Suppl):224, 1997.

Exemplary methods of making a recombinant human IL-10 are described inPajkrt et al., J. Immunol. 158: 3971-3977, 1997). Additional exemplarymethods of making recombinant IL-10 are described herein and are knownin the art.

In some embodiments, a recombinant IL-10 is a pegylated recombinantIL-10 (e.g., pegylated recombinant human IL-10) (e.g., a 5 kDaN-terminally PEGylated form of IL-10; AM0010) (Infante et al., ASCOMeeting Abstracts 33(15_suppl):3017, 2015; Chan et al., PLoS One11(6):e0156229, 2016; Mumm et al., Cancer Cell 20(6): 781-796, 2011;Teng et al., Cancer Cell 20(6):691-693, 2011; U.S. Pat. Nos. 8,691,205;8,865,652; 9,259,478; and 9,364,517; and U.S. Patent ApplicationPublication Nos. 2008/0081031; 2009/0214471; 2011/0250163; 2011/0091419;2014/0227223; 2015/0079031; 2015/0086505; 2016/0193352; 2016/0367689;2016/0375101; and 2016/0166647).

In some embodiments, a recombinant IL-10 is a stabilized isoform of arecombinant IL-10. In some embodiments, the stabilized isoform of arecombinant IL-10 is a viral IL-10 protein (e.g., a humancytomegalovirus IL10 (e.g., cmv-IL10, LA-cmv-IL-10 (e.g., Lin et al.,Virus Res. 131(2):213-223, 2008; Jenkins et al., J. Virol.78(3):1440-1447, 2004; Kotenko et al., Proc. Natl. Acad. Sci. U.S.A.97(4):1695-1700, 2000; Jones et al., Proc. Natl. Acad. Sci. U.S.A.99(14):9404-9409, 2002) or a latency-associated viral IL-10 protein(e.g., Poole et al., J. Virol. 88(24):13947-13955, 2014).

In some embodiments, the recombinant IL-10 is a mammalian IL-10 homolog(see, e.g., WO 00/073457). In some embodiments, a mammalian IL-10homolog is BCRF1, an EBV homolog of human IL-10, also known as viralIL-10, or a variant thereof (Liu et al., J. Immunol. 158(2):604-613,1997).

Cells Producing a Recombinant IL-10

In some embodiments, any of the devices or compositions described hereincan include a recombinant cell (e.g., a recombinant mammalian cell) thatsecretes a recombinant IL-10 (e.g., any of the recombinant IL-10proteins described herein). In some embodiments, any of the devices orcompositions described herein can include a cell (e.g., a mammaliancell) that secretes IL-10 (e.g., human IL-10). In some embodiments, themammalian cell can be a mammalian cell obtained from the subject, andafter introduction of a nucleic acid encoding the recombinant IL-10(e.g., any of the recombinant IL-10 proteins described herein) into thecell obtained from the subject, the cell is incorporated into any of thecompositions or devices described herein.

Non-limiting examples of methods that can be used to introduce a vectoror a nucleic acid into a cell (e.g., a mammalian cell) includelipofection, transfection, electroporation, microinjection, calciumphosphate transfection, dendrimer-based transfection, cationic polymertransfection, cell squeezing, sonoporation, optical transfection,impalection, hydrodynamic delivery, magnetofection, viral transduction(e.g., adenoviral and lentiviral transduction), and nanoparticletransfection. These and other methods of introducing a vector or anucleic acid into a cell are well known in the art.

In some examples, the recombinant mammalian cell can be a ChineseHamster Ovary (CHO) cell, a B cell, a CD8⁺ T cell, a dendritic cell, akeratinocyte or an epithelial cell. See, e.g., Mosser et al., Immunol.Rev. 226:205-218, 2009; Fillatreau et al., Nat. Rev. Immunol. 8:391-397,2008; Ryan et al., Crit. Rev. Immunol. 27:15-32, 2007; Moore et al.,Annu. Rev. Immunol. 19:683-765, 2001. In some embodiments, therecombinant mammalian cell can be a mesenchymal stem cell (e.g., Gupteet al., Biomed. J. 40(1):49-54, 2017).

Additional Examples of IL-10 Inhibitors

In some embodiments, the recombinant cell is a recombinant Gram-positivebacterial cell (e.g., a genetically modified Lactococcus lactis(LL-Thy12) (see, e.g., Steidler et al., Science 289:1352-1355, 2000;Braat et al., Clin. Gastroenterol. Heptal. 4:754-759, 2006). In someembodiments, the recombinant cell is a recombinant Gram-negativebacterial cell (e.g., a Shigella flexneri cell) that secretes an IL-10receptor agonist (e.g., a recombinant IL-10 protein) (Chamekh et al., J.Immunol. 180(6): 4292-4298, 2008).

In some embodiments, the IL-10 receptor agonist is a cell (e.g., aClostridium butyricum cell) that induces IL-10 production and secretionby a different cell (e.g., a macrophage) (e.g., Hayashi et al., CellHost Microbe 13:711-722, 2013). In some embodiments, the IL-10 receptoragonist is a recombinant bacterial cell (e.g., a Lactobacillusacidophilus cell) that is deficient in lipoteichoic acid and inducesIL-10 production and secretion by a different cell (e.g., a dendriticcell) (e.g., Mohamadzadeh et al., Proc. Natl. Acad. Sci. U.S.A.108(suppl 1):4623-4630, 2011; Konstantinov et al., Proc. Natl. Acad.Sci. U.S.A. 105(49):19474-9, 2008). In some embodiments, the IL-10receptor agonist is a bacterial cell or a fragment of a bacterial cellthat is maintained in the supernatant that induces IL-10 secretion in adifferent cell (e.g., an immune cell) (e.g., a Faecalibacteriumprausnitzii cell or a Faecalibacterium prausnitzii supernatant) (see,e.g., Sokol et al., Proc. Natl. Acad. Sci. U.S.A. 105(43):16731-16736,2008).

Additional examples of other IL-10 receptor agonists are described in,e.g., U.S. Pat. No. 6,936,586; WO 96/01318; WO 91/00349; WO 13/130913;each incorporated in its entirety herein.

IL-12/IL-23 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is an IL-12/IL-23 inhibitor. The term“IL-12/IL-23 inhibitor” refers to an agent which decreases IL-12 orIL-23 expression and/or the ability of IL-12 to bind to an IL-12receptor or the ability of IL-23 to bind to an IL-23 receptor. In someembodiments, the IL-12/IL-23 inhibitory agent targets IL-12B (p40)subunit. In some embodiments, the IL-12/IL-23 inhibitory agent targetsIL-12A (p35). In some embodiments, the IL-12/IL-23 inhibitory agenttargets IL-23 (p19). In some embodiments, the IL-12/IL-23 inhibitoryagent targets the receptor for IL-12 (one or both of IL-12R β1 or IL-12Rβ2). In some embodiments, the IL-12/IL-23 inhibitory agent targets thereceptor for IL-23 (one or both of IL-12R β1 and IL-23R).

In some embodiments, an IL-12/IL-23 inhibitor can be an inhibitorynucleic acid. In some embodiments, the inhibitory nucleic acid can be anantisense nucleic acid, a ribozyme, and a small interfering RNA (siRNA).

Non-limiting examples of siRNAs targeting IL-12A (p35), IL-12B (p40),IL-23 (p19), IL-12R β1, IL-12R β2, or IL-23R are described in Tan etal., J. Alzheimers Dis. 38(3): 633-646, 2014; Niimi et al., J.Neuroimmunol. 254(1-2):39-45, 2013. Non-limiting examples of shorthairpin RNA (shRNA) targeting IL-12A (p35), IL-12B (p40), IL-23 (p19),IL-12R β1, IL-12R β2, or IL-23R are described in Bak et al., BMCDermatol. 11:5, 2011.

Non-limiting examples of inhibitory nucleic acids are microRNAs (e.g.,microRNA-29 (Brain et al., Immunity 39(3):521-536, 2013), miR-10a (Xueet al., J. Immunol. 187(11):5879-5886, 2011), microRNA-155 (Podsiad etal., Am. J. Physiol. Lung Cell Mol. Physiol. 310(5):L465-75, 2016).

IL-12/IL-23 Inhibitor Antibodies

In some embodiments, the IL-12/IL-23 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment described hereinbinds specifically to any one of IL-12A (p35), IL-12B (p40), IL-23(p19), IL-12R β1, IL-12R β2, or IL-23R, or a combination thereof.

In some embodiments, the antibody is ustekinumab (CNTO 1275, Stelara®)or a variant thereof (Krueger et al., N. Engl. J. Med. 356(6):580-592,2007; Kauffman et al., J. Invest. Dermatol. 123(6):1037-1044, 2004;Gottlieb et al., Curr. Med. Res. Opin. 23(5):1081-1092, 2007; Leonardiet al., Lancet 371(9625):1665-1674, 2008; Papp et al., Lancet371(9625):1675-1684, 2008). In some embodiments, the antibody isbriakinumab (ABT-874, J-695) or a variant thereof (Gordon et al., J.Invest. Dermatol. 132(2):304-314, 2012; Kimball et al., Arch Dermatol.144(2): 200-207, 2008).

In some embodiments, the antibody is guselkumab (CNTO-1959)(Callis-Duffin et al., J. Am. Acad. Dermatol. 70(5 Suppl 1), 2014);AB162 (Sofen et al., J. Allergy Clin. Immunol. 133: 1032-40, 2014);tildrakizumab (MK-3222, SCH900222) (Papp et al. (2015) Br. J. Dermatol.2015); Langley et al., Oral Presentation at: American Academy ofDermatology, March 21-25, Denver Colo., 2014); AMG 139 (MEDI2070,brazikumab) (Gomollon, Gastroenterol. Hepatol. 38(Suppl. 1):13-19, 2015;Kock et al., Br. J. Pharmacol. 172(1):159-172, 2015); FM-202 (Tang etal., Immunology 135(2):112-124, 2012); FM-303 (Tang et al., Immunology135(2):112-124, 2012); ADC-1012 (Tang et al., Immunology 135(2):112-124,2012); LY-2525623 (Gaffen et al., Nat. Rev. Immunol. 14:585-600, 2014;Sands, Gastroenterol. Hepatol. 12(12):784-786, 2016), LY-3074828 (Coskunet al., Trends Pharmacol. Sci. 38(2):127-142, 2017), BI-655066(risankizumab) (Singh et al., MAbs 7(4):778-791, 2015; Krueger et al.,J. Allergy Clin. Immunol. 136(1):116-124, 2015) or a variant thereof.

Further teachings of IL-12/IL-23 antibodies and antigen-bindingfragments thereof are described in U.S. Pat. Nos. 6,902,734; 7,247,711;7,252,971; and 7,491,391; US 2012/0288494; and US 2013/0302343, each ofwhich is incorporated by reference in its entirety.

In some embodiments, the IL-12/IL-23 inhibitor is PTG-200, an IL-23Rinhibitor currently in preclinical development by ProtagonistTherapeutics.

In some embodiments, the IL-12/IL-23 inhibitor is Mirikizumab (LY3074828), an IL-23R inhibitor currently in clinical development (PhaseII) by Eli Lilly.

In some embodiments, the IL-12/IL-23 inhibitor is AK-101.

IL-12/IL-23 Inhibitor Fusion Proteins

In some embodiments, the IL-12/IL-23 inhibitor is a fusion protein, asoluble antagonist, or an antimicrobial peptide. In some embodiments,the fusion protein comprises a soluble fragment of a receptor of IL-12or a soluble fragment of a receptor of IL-23. In some embodiments, thefusion protein comprises an extracellular domain of a receptor of IL-12or an extracellular domain of a receptor of IL-23.

In some embodiments, the fusion protein is adnectin or a variant thereof(Tang et al., Immunology 135(2):112-124, 2012). In some embodiments, thesoluble antagonist is a human IL-23Ra-chain mRNA transcript (Raymond etal., J. Immunol. 185(12):7302-7308, 2010). In some embodiments, theIL-12/IL-23 is an antimicrobial peptide (e.g., MP-196 (Wenzel et al.,PNAS 111(14):E1409-E1418, 2014)).

IL-12/IL-23 Inhibitor Small Molecules

In some embodiments, the IL-12/IL-23 inhibitor is a small molecule. Insome embodiments, the small molecule is STA-5326 (apilimod) or a variantthereof (Keino et al., Arthritis Res. Ther. 10: R122, 2008; Wada et al.,Blood 109(3):1156-1164, 2007; Sands et al., Inflamm. Bowel Dis.16(7):1209-1218, 2010).

IL-13 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is an IL-13 inhibitor. The term “IL-13inhibitor” refers to an agent which decreases IL-13 expression and/ordecreases the binding of IL-13 to an IL-13 receptor. In someembodiments, the IL-13 inhibitor decreases the ability of IL-13 to bindan IL-13 receptor (e.g., a complex including IL-4Ra and IL-13Rα1, or acomplex including IL-13Rα1 and IL-13Rα2).

In some embodiments, an IL-13 inhibitor is an inhibitory nucleic acid,an antibody or an antigen-binding fragment thereof, or a fusion protein.In some embodiments, the inhibitory nucleic acid can be an antisensenucleic acid, a ribozyme, a small interfering RNA, a small hairpin RNA,or a microRNA. Examples of aspects of these different inhibitory nucleicacids are described below. Any of the examples of inhibitory nucleicacids that can decrease expression of an IL-13, IL-13Rα1, IL-13Rα2, orIL-4Rα mRNA in a mammalian cell can be synthesized in vitro.

Non-limiting examples of short interfering RNA (siRNA) that are IL-13inhibitors are described in Lively et al., J. Allergy Clin. Immunol.121(1):88-94, 2008). Non-limiting examples of short hairpin RNA (shRNA)that are IL-13 inhibitors are described in Lee et al., Hum Gene Ther.22(5):577-586, 2011, and Shilovskiy et al., Eur. Resp. J. 42:P523,2013).

In some embodiments, an inhibitory nucleic acid can be a microRNA.Non-limiting examples of microRNAs that are IL-13 inhibitors are let-7(Kumar et al., J. Allergy Clin. Immunol. 128(5):1077-1085, 2011).

IL-13 Inhibitor Antibodies

In some embodiments, the IL-13 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment described hereinbinds specifically to any one of IL-13, IL-13Rα1, IL-13Rα2, or IL-4Rα,or a combination thereof. In some embodiments, an antibody orantigen-binding fragment of an antibody described herein can bindspecifically to IL-13. In some embodiments, an antibody orantigen-binding fragment of an antibody described herein can bindspecifically to an IL-13 receptor (e.g., a complex including IL-4Rα andIL-13Rα1, or a complex including IL-13Rα1 and IL-13Rα2).

In some embodiments, the IL-13 inhibitor is a monoclonal antibody(Bagnasco et al., Int. Arch. Allergy Immunol. 170:122-131, 2016). Insome embodiments, the IL-13 inhibitor is QAX576 (Novartis) or anantigen-binding fragment thereof (see, e.g., Kariyawasam et al., B92 NewTreatment Approaches for Asthma and Allergy San Diego, 2009; Rothenberget al., J. Allergy Clin. Immunol. 135:500-507, 2015). In someembodiments, the IL-13 inhibitor is ABT-308 (Abbott) or anantigen-binding fragment thereof (see, e.g., Ying et al., AmericanThoracic Society 2010 International Conference, May 14-19, 2010, NewOrleans; Abstract A6644). In some embodiments, the IL-13 inhibitor isCNTO-5825 (Centrocore) or an antigen-binding fragment thereof (see,e.g., van Hartingsveldt et al., British J. Clin. Pharmacol.75:1289-1298, 2013). In some embodiments, the IL-13 inhibitor isdupilumab (REGN668/SAR231893) or an antigen-binding fragment thereof(see, e.g., Simpson et al., N. Eng. J. Med. 375:2335-2348, 2016; Thaciet al., Lancet 387:40-52, 2016). In some embodiments, the IL-13inhibitor is AMG317 (Amgen) or an antigen-binding fragment thereof(Polosa et al., Drug Discovery Today 17:591-599, 2012; Holgate, BritishJ. Clinical Pharmacol. 76:277-291, 2013). In some embodiments, the IL-13inhibitor is an antibody that specifically binds to IL-13Rα1 (see, e.g.,U.S. Pat. No. 7,807,158; WO 96/29417; WO 97/15663; and WO 03/080675).

In some embodiments, the IL-13 inhibitor is a humanized monoclonalantibody (e.g., lebrikizumab (TNX-650) (Thomson et al., Biologics6:329-335, 2012; and Hanania et al., Thorax 70(8):748-756, 2015). Insome embodiments, the IL-13 inhibitor is an anti-IL-13 antibody, e.g.,GSK679586 or a variant thereof (Hodsman et al., Br. J. Clin. Pharmacol.75(1):118-128, 2013; and De Boever et al., J. Allergy Clin. Immunol.133(4):989-996, 2014). In some embodiments, the IL-13 inhibitor istralokinumab (CAT-354) or a variant thereof (Brightling et al., Lancet3(9): 692-701, 2015; Walsh et al. (2010) Curr. Opin. Investig. Drugs11(11):1305-1312, 2010; Piper et al., Euro. Resp. J. 41:330-338, 2013;May et al., Br. J. Pharmacol. 166(1): 177-193, 2012; Singh et al., BMCPulm Med. 10:3, 2010; Blanchard et al., Clin. Exp. Allergy 35(8):1096-1103, 2005). In some embodiments, the Il-13 inhibitor isanrukinzumab (IMA-638) (Hua et al., Br. J. Clin. Pharmacol. 80: 101-109,2015; Reinisch et al., Gut 64(6): 894-900, 2015; Gauvreau et al., Am. J.Respir. Crit. Care Med. 183(8):1007-1014, 2011; Bree et al., J. AllergyClin. Immunol. 119(5):1251-1257, 2007). Further teachings of IL-13inhibitors that are antibodies or antigen-binding fragments thereof aredescribed in U.S. Pat. Nos. 8,067,199; 7,910,708; 8,221,752; 8,388,965;8,399,630; and 8,734,801; US 2014/0341913; US 2015/0259411; US2016/0075777; US 2016/0130339, US 2011/0243928, and US 2014/0105897 eachof which is incorporated by reference in its entirety.

IL-13 Inhibitor Fusion Proteins

In some embodiments, the IL-13 inhibitor is a fusion protein or asoluble antagonist. In some embodiments, the fusion protein comprises asoluble fragment of a receptor of IL-13 (e.g., a soluble fragment of acomplex including IL-13Rα1 and IL-4Rα, a soluble fragment of a complexincluding IL-13Rα1 and IL-13Rα2, a soluble fragment of IL-13Rα1, asoluble fragment of IL-13Rα2, or soluble fragment of IL-4Rα). In someembodiments, the fusion protein comprises an extracellular domain of areceptor of IL-13 (e.g., a fusion protein including an extracellulardomain of both IL-13Rα1 and IL-4Rα, a fusion protein including anextracellular domain of both IL-13Rα1 and IL-13Rα2, a fusion proteinincluding an extracellular domain of IL-13Rα1, a fusion proteinincluding an extracellular domain of IL-13Rα2, or a fusion proteinincluding an extracellular domain of IL-4Rα).

In some embodiments, the fusion protein comprises or consists ofsIL-13Rα2-Fc (see, e.g., Chiaramonte et al., J. Clin. Invest.104(6):777-785, 1999; Kasaian et al., Am. J. Respir. Cell. Mol. Biol.36(3):368-376, 2007; Miyahara et al., J. Allergy Clin. Immunol.118(5):1110-1116, 2006; Rahaman et al., Cancer Res. 62(4):1103-1109,2002; incorporated by reference herein). In some embodiments, the fusionprotein comprises or consists of an IL-13 fusion cytotoxin (e.g.,IL-13/diphtheria toxin fusion protein (Li et al., Protein Eng.15(5):419-427, 2002), IL-13-PE38QQR (IL-13-PE) (Blease et al. (2001) J.Immunol. 167(11):6583-6592, 2001; and Husain et al., J. Neuro-Oncol.65(1):37-48, 2003)).

CD3 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CD3 inhibitor. The term “CD3inhibitor” refers to an agent which decreases the ability of one or moreof CD3K, CD38, CD3c, and CD3 to associate with one or more of TCR-α,TCR-β, TCR-δ, and TCR-K. In some embodiments, the CD3 inhibitor candecrease the association between one or more of CD3K, CD38, CD3c, andCD3ζ and one or more of TCR-α, TCR-β, TCR-δ, and TCR-K by blocking theability of one or more of CD3K, CD3δ, CD3ε, and CD3ζ to interact withone or more of TCR-α, TCR-β, TCR-δ, and TCR-K.

In some embodiments, the CD3 inhibitor is an antibody or anantigen-binding fragment thereof, a fusion protein, or a small molecule.Exemplary CD3 inhibitors are described herein. Additional examples ofCD3 inhibitors are known in the art.

CD3 Inhibitor Antibodies

In some embodiments, the CD3 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, the CD3 inhibitor is an antibody or antigen-bindingfragment that binds specifically to CD3K. In some embodiments, the CD3inhibitor is an antibody or antigen-binding fragment that bindsspecifically to CD38. In some embodiments, the CD3 inhibitor is anantibody or antigen-binding fragment that binds specifically to CD3ε. Insome embodiments, the CD3 inhibitor is an antibody or antigen-bindingfragment that binds specifically to CD3ζ. In some embodiments, the CD3inhibitor is an antibody or an antigen-binding fragment that can bind totwo or more (e.g., two, three, or four) of CD3K, CD3δ, CD3ε, and CD3ζ.

In certain embodiments, the antibody comprises or consists of anantigen-binding fragment or portion of visiluzumab (Nuvion; HuM-291;M291; SMART anti-CD3 antibody) (Carpenter et al., Biol. Blood MarrowTransplant 11(6): 465-471, 2005; Trajkovic Curr. Opin. Investig. Drugs3(3): 411-414, 2002; Malviya et al., J. Nucl. Med. 50(10): 1683-1691,2009); muromonab-CD3 (orthoclone OKT3) (Hori et al., Surg. Today 41(4):585-590, 2011; Norman Ther. Drug Monit. 17(6): 615-620, 1995; andGramatzki et al., Leukemia 9(3): 382-390, 19); otelixizumab (TRX4)(Vossenkamper et al., Gastroenterology 147(1): 172-183, 2014; andWiczling et al., J. Clin. Pharmacol. 50(5): 494-506, 2010); foralumab(NI-0401) (Ogura et al., Clin. Immunol. 183: 240-246; and van der Woudeet al., Inflamm. Bowel Dis. 16: 1708-1716, 2010); ChAgly CD3; teplizumab(MGA031) (Waldron-Lynch et al., Sci. Transl. Med. 4(118): 118ra12, 2012;and Skelley et al., Ann. Pharmacother. 46(10): 1405-1412, 2012); orcatumaxomab (Removab®) (Linke et al., Mabs 2(2): 129-136, 2010; andBokemeyer et al., Gastric Cancer 18(4): 833-842, 2015).

Additional examples of CD3 inhibitors that are antibodies or antibodyfragments are described in, e.g., U.S. Patent Application PublicationNos. 2017/0204194, 2017/0137519, 2016/0368988, 2016/0333095,2016/0194399, 2016/0168247, 2015/0166661, 2015/0118252, 2014/0193399,2014/0099318, 2014/0088295, 2014/0080147, 2013/0115213, 2013/0078238,2012/0269826, 2011/0217790, 2010/0209437, 2010/0183554, 2008/0025975,2007/0190045, 2007/0190052, 2007/0154477, 2007/0134241, 2007/0065437,2006/0275292, 2006/0269547, 2006/0233787, 2006/0177896, 2006/0165693,2006/0088526, 2004/0253237, 2004/0202657, 2004/0052783, 2003/0216551,and 2002/0142000, each of which is herein incorporated by reference inits entirety (e.g., the sections describing the CD3 inhibitors).Additional CD3 inhibitors that are antibodies or antigen-bindingantibody fragments are described in, e.g., Smith et al., J. Exp. Med.185(8):1413-1422, 1997; Chatenaud et al., Nature 7:622-632, 2007.

In some embodiments, the CD3 inhibitor comprises or consists of abispecific antibody (e.g., JNJ-63709178) (Gaudet et al., Blood 128(22):2824, 2016); JNJ-64007957 (Girgis et al., Blood 128: 5668, 2016); MGD009(Tolcher et al., J. Clin. Oncol. 34:15, 2016); ERY974 (Ishiguro et al.,Sci. Transl. Med. 9(410): pii.eaa14291, 2017); AMV564 (Hoseini andCheung Blood Cancer J. 7:e522, 2017); AFM11 (Reusch et al., MAbs 7(3):584-604, 2015); duvortuxizumab (JNJ 64052781); R06958688; blinatumomab(Blincyto®; AMG103) (Ribera Expert Rev. Hematol. 1:1-11, 2017; and Moriet al., N Engl. J. Med. 376(23):e49, 2017); XmAb13676; or REGN1979(Bannerji et al., Blood 128: 621, 2016; and Smith et al., Sci. Rep.5:17943, 2015)).

In some embodiments, the CD3 inhibitor comprises or consists of atrispecific antibody (e.g., ertumaxomab (Kiewe and Thiel, Expert Opin.Investig. Drugs 17(10): 1553-1558, 2008; and Haense et al., BMC Cancer16:420, 2016); or FBTA05 (Bi20; Lymphomun) (Buhmann et al., J. Transl.Med. 11:160, 2013; and Schuster et al., Br. J. Haematol. 169(1): 90-102,2015)).

CD3 Inhibitor Fusion and Truncated Proteins and Peptides

In some embodiments, the CD3 inhibitor is a fusion protein, a truncatedprotein (e.g., a soluble receptor), or a peptide. In some embodiments,the CD3 inhibitor can be a fusion protein (see, e.g., Lee et al., Oncol.Rep. 15(5): 1211-1216, 2006).

CD3 Inhibitor Small Molecules

In some embodiments, the CD3 inhibitor comprises or consists of abispecific small molecule-antibody conjugate (see, e.g., Kim et al.,PNAS 110(44): 17796-17801, 2013; Viola et al., Eur. J. Immunol.27(11):3080-3083, 1997).

CD14 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CD14 inhibitor. The term “CD14inhibitors” refers to an agent which decreases the ability of CD14 tobind to lipopolysaccharide (LPS). CD14 acts as a co-receptor withToll-like receptor 4 (TLR4) that binds LPS in the presence oflipopolysaccharide-binding protein (LBP).

In some embodiments, the CD14 inhibitor can decrease the binding betweenCD14 and LPS by blocking the ability of CD14 to interact with LPS.

In some embodiments, the CD14 inhibitor is an antibody or anantigen-binding fragment thereof. In some embodiments, the CD14inhibitor is a small molecule. Exemplary CD14 inhibitors are describedherein. Additional examples of CD14 inhibitors are known in the art.

CD14 Inhibitor Antibodies

In some embodiments, the CD14 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, the CD14 inhibitor is an antibody or antigen-bindingfragment that binds specifically to CD14.

In certain embodiments, the antibody comprises or consists of anantigen-binding fragment or portion of IC14 (Axtelle and Pribble, J.Endotoxin Res. 7(4): 310-314, 2001; Reinhart et al., Crit. Care Med.32(5): 1100-1108, 2004; Spek et al., J. Clin. Immunol. 23(2): 132-140,2003). Additional examples of anti-CD14 antibodies and CD14 inhibitorscan be found, e.g., in WO 2015/140591 and WO 2014/122660, incorporatedin its entirety herein.

Additional examples of CD14 inhibitors that are antibodies or antibodyfragments are described in, e.g., U.S. Patent Application Serial No.2017/0107294, 2014/0050727, 2012/0227412, 2009/0203052, 2009/0029396,2008/0286290, 2007/0106067, 2006/0257411, 2006/0073145, 2006/0068445,2004/0092712, 2004/0091478, and 2002/0150882, each of which is hereinincorporated by reference (e.g., the sections that describe CD14inhibitors).

CD14 Inhibitor Small Molecules

In some embodiments, the CD14 inhibitor is a small molecule.Non-limiting examples of CD14 inhibitors that are small molecules aredescribed in, e.g., methyl 6-deoxy-6-N-dimethyl-N-cyclopentylammonium-2,3-di-O-tetradecyl-α-D-glucopyranoside iodide (IAXO-101); methyl6-Deoxy-6-amino-2,3-di-O-tetradecyl-α-D-glucopyranoside (IAXO-102);N-(3,4-bis-tetradecyloxy-benzyl)-N-cyclopentyl-N,N-dimethylammoniumiodide (IAXO-103); and IMO-9200.

CD20 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CD20 inhibitor. The term “CD20inhibitors” refers to an agent that binds specifically to CD20 expressedon the surface of a mammalian cell.

In some embodiments, the CD20 inhibitor is an antibody or anantigen-binding fragment thereof, or a fusion protein or peptide.Exemplary CD20 inhibitors are described herein. Additional examples ofCD20 inhibitors are known in the art.

CD20 Inhibitor Antibodies

In some embodiments, the CD20 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv).

In certain embodiments, the antibody comprises or consists of anantigen-binding fragment or portion of rituximab (Rituxan®, MabThera®,MK-8808) (Ji et al., Indian J. Hematol. Blood Transfus. 33(4): 525-533,2017; and Calderon-Gomez and Panes Gastroenterology 142(1): 1741-76,2012);—PF-05280586; ocrelizumab (Ocrevus™) (Sharp N. Engl. J. Med.376(17): 1692, 2017); ofatumumab (Arzerra®; HuMax-CD20) (AlDallal Ther.Clin. Risk Manag. 13:905-907, 2017; and Furman et al., Lancet Haematol.4(1): e24-e34, 2017); PF-05280586 (Williams et al., Br. J. Clin.Pharmacol. 82(6): 1568-1579, 2016; and Cohen et al., Br. J. Clin.Pharmacol. 82(1): 129-138, 2016); obinutuzumab (Gazyva®) (Reddy et al.,Rheumatology 56(7): 1227-1237, 2017; and Marcus et al., N. Engl. J. Med.377(14): 1331-1344, 2017); ocaratuzumab (AME-133v; LY2469298) (Cheney etal., Mabs 6(3): 749-755, 2014; and Tobinai et al., Cancer Sci. 102(2):432-8, 2011); GP2013 (Jurczak et al., Lancet Haenatol. 4(8): e350-e361,2017); IBI301; HLX01; veltuzumab (hA20) (Kalaycio et al., Leuk. Lymphoma57(4): 803-811, 2016; and Ellebrecht et al., JAMA Dermatol. 150(12):1331-1335, 2014); SCT400 (Gui et al., Clin. J. Cancer Res. 28(2):197-208); ibritumomab tiuxetan (Zevalin®) (Philippe et al., Bone MarrowTransplant 51(8): 1140-1142, 2016; and Lossos et al., Leuk. Lymphoma56(6): 1750-1755, 2015); ublituximab (TG1101) (Sharman et al., Blood124: 4679, 2014; and Sawas et al., Br. J. Haematol. 177(2): 243-253,2017); LFB-R603 (Esteves et al., Blood 118: 1660, 2011; and Baritaki etal., Int. J. Oncol. 38(6): 1683-1694, 2011); or tositumomab (Bexxar)(Buchegger et al., J. Nucl. Med. 52(6): 896-900, 2011; and William andBierman Expert Opin. Biol. Ther. 10(8): 1271-1278, 2010). Additionalexamples of CD20 antibodies are known in the art (see, e.g., WO2008/156713).

In certain embodiments, the antibody comprises or consists of anantigen-binding fragment or portion of a bispecific antibody (e.g.,XmAb13676; REGN1979 (Bannerji et al., Blood 128: 621, 2016; and Smith etal., Sci. Rep. 5: 17943, 2015); PRO131921 (Casulo et al., Clin. Immnol.154(1): 37-46, 2014; and Robak and Robak BioDrugs 25(1): 13-25, 2011);or Acellbia).

In some embodiments, the CD20 inhibitor comprises or consists of atrispecific antibody (e.g., FBTA05 (Bi20; Lymphomun) (Buhmann et al., J.Transl. Med. 11:160, 2013; and Schuster et al., Br. J. Haematol. 169(1):90-102, 2015)).

Additional examples of CD20 inhibitors that are antibodies orantigen-binding fragments are described in, e.g., U.S. PatentApplication Publication Nos. 2017/0304441, 2017/0128587, 2017/0088625,2017/0037139, 2017/0002084, 2016/0362472, 2016/0347852, 2016/0333106,2016/0271249, 2016/0243226, 2016/0115238, 2016/0108126, 2016/0017050,2016/0017047, 2016/0000912, 2016/0000911, 2015/0344585, 2015/0290317,2015/0274834, 2015/0265703, 2015/0259428, 2015/0218280, 2015/0125446,2015/0093376, 2015/0079073, 2015/0071911, 2015/0056186, 2015/0010540,2014/0363424, 2014/0356352, 2014/0328843, 2014/0322200, 2014/0294807,2014/0248262, 2014/0234298, 2014/0093454, 2014/0065134, 2014/0044705,2014/0004104, 2014/0004037, 2013/0280243, 2013/0273041, 2013/0251706,2013/0195846, 2013/0183290, 2013/0089540, 2013/0004480, 2012/0315268,2012/0301459, 2012/0276085, 2012/0263713, 2012/0258102, 2012/0258101,2012/0251534, 2012/0219549, 2012/0183545, 2012/0100133, 2012/0034185,2011/0287006, 2011/0263825, 2011/0243931, 2011/0217298, 2011/0200598,2011/0195022, 2011/0195021, 2011/0177067, 2011/0165159, 2011/0165152,2011/0165151, 2011/0129412, 2011/0086025, 2011/0081681, 2011/0020322,2010/0330089, 2010/0310581, 2010/0303808, 2010/0183601, 2010/0080769,2009/0285795, 2009/0203886, 2009/0197330, 2009/0196879, 2009/0191195,2009/0175854, 2009/0155253, 2009/0136516, 2009/0130089, 2009/0110688,2009/0098118, 2009/0074760, 2009/0060913, 2009/0035322, 2008/0260641,2008/0213273, 2008/0089885, 2008/0044421, 2008/0038261, 2007/0280882,2007/0231324, 2007/0224189, 2007/0059306, 2007/0020259, 2007/0014785,2007/0014720, 2006/0121032, 2005/0180972, 2005/0112060, 2005/0069545,2005/0025764, 2004/0213784, 2004/0167319, 2004/0093621, 2003/0219433,2003/0206903, 2003/0180292, 2003/0026804, 2002/0039557, 2002/0012665,and 2001/0018041, each herein incorporated by reference in theirentirety (e.g., sections describing CD20 inhibitors).

CD20 Inhibitor Peptides and Fusion Proteins

In some embodiments, the CD20 inhibitor is an immunotoxin (e.g., MT-3724(Hamlin Blood 128: 4200, 2016).

In some embodiments, the CD20 inhibitor is a fusion protein (e.g.,TRU-015 (Rubbert-Roth Curr. Opin. Mol. Ther. 12(1): 115-123, 2010).Additional examples of CD20 inhibitors that are fusion proteins aredescribed in, e.g., U.S. Patent Application Publication Nos.2012/0195895, 2012/0034185, 2009/0155253, 2007/0020259, and2003/0219433, each of which are herein incorporated by reference intheir entirety (e.g., sections describing CD20 inhibitors).

CD25 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CD25 inhibitor. The term “CD25inhibitors” refers to an agent which decreases the ability of CD25 (alsocalled interleukin-2 receptor alpha chain) to bind to interleukin-2.CD25 forms a complex with interleukin-2 receptor beta chain andinterleukin-2 common gamma chain.

In some embodiments, the CD25 inhibitor is an antibody or anantigen-binding fragment thereof, or a fusion protein. Exemplary CD25inhibitors are described herein. Additional examples of CD25 inhibitorsare known in the art.

CD25 Inhibitor Antibodies

In some embodiments, the CD25 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, a CD25 inhibitor is an antibody or an antigen-bindingfragment thereof that specifically binds to CD25. In some embodiments, aCD25 inhibitor is an antibody that specifically binds to IL-2.

In certain embodiments, the antibody comprises or consists of anantigen-binding fragment or portion of basiliximab (Simulect™) (Wang etal., Clin. Exp. Immunol. 155(3): 496-503, 2009; and Kircher et al.,Clin. Exp. Immunol. 134(3): 426-430, 2003); daclizumab (Zenapax;Zinbryta®) (Berkowitz et al., Clin. Immunol. 155(2): 176-187, 2014; andBielekova et al., Arch Neurol. 66(4): 483-489, 2009); or IMTOX-25.

In some embodiments, the CD25 inhibitor is an antibody-drug-conjugate(e.g., ADCT-301 (Flynn et al., Blood 124: 4491, 2014)).

Additional examples of CD25 inhibitors that are antibodies are known inthe art (see, e.g., WO 2004/045512). Additional examples of CD25inhibitors that are antibodies or antigen-binding fragments aredescribed in, e.g., U.S. Patent Application Publication Nos.2017/0240640, 2017/0233481, 2015/0259424, 2015/0010539, 2015/0010538,2012/0244069, 2009/0081219, 2009/0041775, 2008/0286281, 2008/0171017,2004/0170626, 2001/0041179, and 2010/0055098, each of which isincorporated herein by reference (e.g., sections that describe CD25inhibitors).

CD25 Inhibitor Fusion Proteins

In some embodiments, the CD25 inhibitor is a fusion protein. See, e.g.,Zhang et al., PNAS 100(4): 1891-1895, 2003.

CD28 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CD28 inhibitor. The term “CD28inhibitors” refers to an agent which decreases the ability of CD28 tobind to one or both of CD80 and CD86. CD28 is a receptor that binds toits ligands, CD80 (also called B7.1) and CD86 (called B7.2).

In some embodiments, the CD28 inhibitor can decrease the binding betweenCD28 and CD80 by blocking the ability of CD28 to interact with CD80. Insome embodiments, the CD28 inhibitor can decrease the binding betweenCD28 and CD86 by blocking the ability of CD28 to interact with CD86. Insome embodiments, the CD28 inhibitor can decrease the binding of CD28 toeach of CD80 and CD86.

In some embodiments, the CD28 inhibitor is an antibody or anantigen-binding fragment thereof, a fusion protein, or peptide.Exemplary CD28 inhibitors are described herein. Additional examples ofCD28 inhibitors are known in the art.

CD28 Inhibitor Antibodies

In some embodiments, the CD28 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv).

In some embodiments, the CD28 inhibitor is a monovalent Fab′ antibody(e.g., CFR104) (Poirier et al., Am. J. Transplant 15(1): 88-100, 2015).

Additional examples of CD28 inhibitors that are antibodies orantigen-binding fragments are described in, e.g., U.S. PatentApplication Publication Nos. 2017/0240636, 2017/0114136, 2016/0017039,2015/0376278, 2015/0299321, 2015/0232558, 2015/0150968, 2015/0071916,2013/0266577, 2013/0230540, 2013/0109846, 2013/0078257, 2013/0078236,2013/0058933, 2012/0201814, 2011/0097339, 2011/0059071, 2011/0009602,2010/0266605, 2010/0028354, 2009/0246204, 2009/0117135, 2009/0117108,2008/0095774, 2008/0038273, 2007/0154468, 2007/0134240, 2007/0122410,2006/0188493, 2006/0165690, 2006/0039909, 2006/0009382, 2006/0008457,2004/0116675, 2004/0092718, 2003/0170232, 2003/0086932, 2002/0006403,2013/0197202, 2007/0065436, 2003/0180290, 2017/0015747, 2012/0100139,and 2007/0148162, each of which is incorporated by reference in itsentirety (e.g., sections that described CD28 inhibitors).

CD28 Inhibitor Fusion Proteins and Peptides

In some embodiments, the CD28 inhibitor is a fusion protein (see, e.g.,U.S. Pat. No. 5,521,288; and US 2002/0018783). In some embodiments, theCD28 inhibitor is abatacept (Orencia®) (Herrero-Beaumont et al.,Rheumatol. Clin. 8: 78-83, 2012; and Korhonen and Moilanen Basic Clin.Pharmacol. Toxicol. 104(4): 276-284, 2009).

In some embodiments, the CD28 inhibitor is a peptide mimetic (e.g.,AB103) (see, e.g., Bulger et al., JAMA Surg. 149(6): 528-536, 2014), ora synthetic peptoid (see, e.g., Li et al., Cell Mol. Immunol. 7(2):133-142, 2010).

CD40/CD40L Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CD40/CD40L inhibitor. The term“CD40/CD40L inhibitors” refers to an agent which decreases CD40 or CD40L(CD154) expression and/or the ability of CD40 to bind to CD40L (CD154).CD40 is a costimulatory receptor that binds to its ligand, CD40L(CD154).

In some embodiments, the CD40/CD40L inhibitor can decrease the bindingbetween CD40 and CD40L by blocking the ability of CD40 to interact withCD40L. In some embodiments, the CD40/CD40L inhibitor can decrease thebinding between CD40 and CD40L by blocking the ability of CD40L tointeract with CD40. In some embodiments, the CD40/CD40L inhibitordecreases the expression of CD40 or CD40L. In some embodiments, theCD40/CD40L inhibitor decreases the expression of CD40. In someembodiments, the CD40/CD40L inhibitor decreases the expression of CD40L.

In some embodiments, the CD40/CD40L inhibitor is an inhibitory nucleicacid, an antibody or an antigen-binding fragment thereof, a fusionprotein, or a small molecule. In some embodiments, the inhibitorynucleic acid is a small interfering RNA, an antisense nucleic acid, anaptamer, or a microRNA. Exemplary CD40/CD40L inhibitors are describedherein. Additional examples of CD40/CD40L inhibitors are known in theart.

Inhibitory Nucleic Acids of CD40/CD40L

Some exemplary antisense nucleic acids that are CD40 or CD40L inhibitorsare described, e.g., in U.S. Pat. Nos. 6,197,584 and 7,745,609; Gao etal., Gut 54(1):70-77, 2005; Arranz et al., J. Control Release165(3):163-172, 2012; Donner et al., Mol. Ther. Nucleic Acids 4:e265,2015.

Non-limiting examples of short interfering RNA (siRNA) that areCD40/CD40L inhibitors are described in, e.g., Pluvinet et al., Blood104:3642-3646, 2004; Karimi et al., Cell Immunol. 259(1):74-81, 2009;and Zheng et al., Arthritis Res. Ther. 12(1):R13, 2010. Non-limitingexamples of short hairpin RNA (shRNA) targeting CD40/CD40L are describedin Zhang et al., Gene Therapy 21:709-714, 2014. Non-limiting examples ofmicroRNAs that are CD40/CD40L inhibitors include, for example, miR146a(Chen et al., FEBS Letters 585(3):567-573, 2011), miR-424, and miR-503(Lee et al., Sci. Rep. 7:2528, 2017).

Non-limiting examples of aptamers that are CD40/CD40L inhibitors aredescribed in Soldevilla et al., Biomaterials 67:274-285, 2015.

CD40/CD40L Inhibitor Antibodies

In certain embodiments, the antibody comprises or consists of anantigen-binding fragment or portion of PG102 (Pangenetics) (Bankert etal., J. Immunol. 194(9):4319-4327, 2015); 2C10 (Lowe et al., Am. J.Transplant 12(8):2079-2087, 2012); ASKP1240 (Bleselumab) (Watanabe etal., Am. J. Transplant 13(8):1976-1988, 2013); 4D11 (Imai et al.,Transplantation 84(8):1020-1028, 2007); BI 655064 (Boehringer Ingelheim)(Visvanathan et al., 2016 American College of Rheumatology AnnualMeeting, Abstract 1588, Sep. 28, 2016); 5D12 (Kasran et al., Aliment.Pharmacol. Thu., 22(2):111-122, 2005; Boon et al., Toxicology174(1):53-65, 2002); ruplizumab (hu5c8) (Kirk et al., Nat. Med.5(6):686-693, 1999); CHIR12.12 (HCD122) (Weng et al., Blood104(11):3279, 2004; Tai et al., Cancer Res. 65(13):5898-5906, 2005);CDP7657 (Shock et al., Arthritis Res. Ther. 17(1):234, 2015); BMS-986004domain antibody (dAb) (Kim et al., Am. J. Transplant. 17(5):1182-1192,2017); 5c8 (Xie et al., J. Immunol. 192(9):4083-4092, 2014); dacetuzumab(SGN-40) (Lewis et al., Leukemia 25(6):1007-1016, 2011; and Khubchandaniet al., Curr. Opin. Investig. Drugs 10(6):579-587, 2009); lucatumumab(HCD122) (Bensinger et al., Br. J. Haematol. 159: 58-66, 2012; and Byrdet al., Leuk. Lymphoma 53(11): 10.3109/10428194.2012.681655, 2012);PG102 (FFP104) (Bankert et al., J. Immunol. 194(9):4319-4327, 2015); ChiLob 7/4 (Johnson et al., J. Clin. Oncol. 28:2507, 2019); and ASKP1240(Okimura et al., Am. J. Transplant. 14(6): 1290-1299, 2014; or Ma etal., Transplantation 97(4): 397-404, 2014).

Further teachings of CD40/CD40L antibodies and antigen-binding fragmentsthereof are described in, for example, U.S. Pat. Nos. 5,874,082;7,169,389; 7,271,152; 7,288,252; 7,445,780; 7,537,763, 8,277,810;8,293,237, 8,551,485; 8,591,900; 8,647,625; 8,784,823; 8,852,597;8,961,976; 9,023,360, 9,028,826; 9,090,696, 9,221,913; US2014/0093497;and US2015/0017155 each of which is incorporated by reference in itsentirety.

CD40/CD40L Inhibitor Fusion and Truncated Proteins and Peptides

In some embodiments, the CD40/CD40L inhibitor is a fusion protein, atruncated protein (e.g., a soluble receptor) or a peptide. In someembodiments, the CD40/CD40L inhibitor is a truncated protein asdisclosed in, for example, WO 01/096397. In some embodiments, theCD40/CD40L inhibitor is a peptide, such as a cyclic peptide (see, e.g.,U.S. Pat. No. 8,802,634; Bianco et al., Org. Biomol. Chem. 4:1461-1463,2006; Deambrosis et al., J. Mol. Med. 87(2):181-197, 2009; Vaitaitis etal., Diabetologia 57(11):2366-2373, 2014). In some embodiments, theCD40/CD40L inhibitor is a CD40 ligand binder, for example, a TumorNecrosis Factor Receptor-associated Factor (TRAF): TRAF2, TRAF3, TRAF6,TRAFS and TTRAP, or E3 ubiquitin-protein ligase RNF128.

CD40/CD40L Inhibitor Small Molecules

In some embodiments, the CD40/CD40L inhibitor is a small molecule (see,e.g., U.S. Pat. No. 7,173,046, U.S. Patent Application No.2011/0065675). In some embodiments, the small molecule is Bio8898(Silvian et al., ACS Chem. Biol. 6(6):636-647, 2011); Suramin(Margolles-Clark et al., Biochem. Pharmacol. 77(7):1236-1245, 2009); asmall-molecule organic dye (Margolles-Clark et al., J. Mol. Med.87(11):1133-1143, 2009; Buchwald et al., J. Mol. Recognit. 23(1):65-73,2010), a naphthalenesulfonic acid derivative (Margolles-Clark et al.,Chem. Biol. Drug Des. 76(4):305-313, 2010), or a variant thereof.

CD49 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CD49 inhibitor. The term “CD49inhibitors” refers to an agent which decreases the ability of CD49 tobind to one of its ligands (e.g., MMP1). In some embodiments, the CD49inhibitor is an antibody or an antigen-binding fragment thereof.Exemplary CD49 inhibitors are described herein. Additional examples ofCD49 inhibitors are known in the art.

CD49 Inhibitor Antibodies

In some embodiments, the CD49 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv).

In certain embodiments, the antibody comprises or consists of anantigen-binding fragment or portion of natalizumab (Tysabri®; Antegren®)(see, e.g., Pagnini et al., Expert Opin. Biol. Ther. 17(11): 1433-1438,2017; and Chataway and Miller Neurotherapeutics 10(1): 19-28, 2013; orvatelizumab (ELND-004)).

CD89 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CD89 inhibitor. The term “CD89inhibitors” refers to an agent which decreases the ability of CD89 tobind to IgA. CD89 is a transmembrane glycoprotein that binds to theheavy-chain constant region of IgA. In some embodiments, the CD89inhibitor can decrease the binding between CD89 and IgA by blocking theability of CD89 to interact with IgA. In some embodiments, the CD89inhibitor is an antibody or an antigen-binding fragment thereof.Exemplary CD89 inhibitors are described herein. Additional examples ofCD89 inhibitors are known in the art.

CD89 Inhibitor Antibodies

In some embodiments, the CD89 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv).

In certain embodiments, the antibody comprises or consists of anantigen-binding fragment or portion of HF-1020. Additional examples ofCD89 antibodies are known in the art (see, e.g., WO 2002/064634).

Integrin Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is an integrin inhibitor. The term“integrin inhibitor” refers to an agent which decreases the expressionof one or more integrins and/or decreases the binding of an integrinligand to one or more integrins that play a role in the recruitment,extravasation, and/or activation of a leukocyte. In some embodiments,the integrin inhibitor specifically binds to at least a portion of aligand binding site on a target integrin. In some embodiments, theintegrin inhibitor specifically binds to a target integrin at the samesite as an endogenous ligand. In some embodiments, the integrininhibitor decreases the level of expression of the target integrin in amammalian cell. In some embodiments, the integrin inhibitor specificallybinds to an integrin ligand.

Non-limiting examples of integrins that can be targeted by any of theintegrin inhibitors described herein include: α2β1 integrin, α1β1integrin, α4β7 integrin, integrin α4β1 (VLA-4), E-selectin, ICAM-1, α5β1integrin, α4β1 integrin, VLA-4, α2β1 integrin, α5β3 integrin, α5β5integrin, αIIbβ3 integrin, and MAdCAM-1. A non-limiting example ofintegrin inhibitor that can decrease the expression and/or activity ofα4β7 integrin is FTY720. A non-limiting example of an integrin inhibitorthat specifically targets MAdCAM is PF-547659 (Pfizer). Non-limitingexamples of an integrin inhibitor that specifically targets α4β7 isAJM300 (Ajinomoto), etrolizumab (Genentech), and vedolizumab(Millenium/Takeda).

In some embodiments, the integrin inhibitor is an αIIbβ3 integrininhibitor. In some embodiments, the αIIbβ3 integrin inhibitor isabciximab (ReoPro®, c7E3; Kononczuk et al., Curr. Drug Targets 16(13):1429-1437, 2015; Jiang et al., Appl. Microbiol. Biotechnol.98(1):105-114, 2014), eptifibatide (Integrilin®; Scarborough et al., J.Biol. Chem. 268:1066-1073, 1993; Tcheng et al., Circulation91:2151-2157, 1995) or tirofiban (Aggrastat®; Hartman et al., J. Med.Chem. 35:4640-4642, 1992; Pierro et al., Eur. J. Ophthalmol.26(4):e74-76, 2016; Guan et al., Eur. J. Pharmacol 761:144-152, 2015).In some embodiments, the integrin inhibitor is an αL-selective integrininhibitor. In some embodiments, the integrin inhibitor is a β2 integrininhibitor.

In some embodiments, the integrin inhibitor is an α4 integrin (e.g., anα4β1 integrin (e.g., Very Late Antigen-4 (VLA-4), CD49d, or CD29))inhibitor, an α4β7 integrin inhibitor. In some embodiments, the integrininhibitor targets endothelial VCAM1, fibronectin, mucosal addressincellular adhesion molecule-1 (MAdCAM-1), vitronectin, tenascin-C,osteopontin (OPN), nephronectin, agiostatin, tissue-typetransglutaminase, factor XIII, Von Willebrand factor (VWF), an ADAMprotein, an ICAM protein, collagen, e-cadherin, laminin, fibulin-5, orTGFβ. In some embodiments, the α4 integrin inhibitor is natalizumab(Tysabri®; Targan et al., Gastroenterology 132(5):1672-1683, 2007;Sandborn et al., N. Engl. J. Med. 353(18):1912-1925, 2005; Nakamura etal., Intern. Med. 56(2):211-214, 2017; and Singh et al., J. Pediatr.Gastroenterol. Nutr. 62(6):863-866, 2016). In some embodiments, theintegrin inhibitor is an endogenous integrin inhibitor (e.g., SHARPIN(Rantala et al., Nat. Cell. Biol. 13(11):1315-1324, 2011).

In some embodiments, the integrin inhibitor is an αv integrin (e.g., anα5β1 integrin, an α5β3 integrin, an α5β5 integrin inhibitor, and/or anα5β6 integrin) inhibitor.

In some embodiments, the integrin inhibitor is an α5β1 integrininhibitor.

In some embodiments, an integrin inhibitor is an inhibitory nucleicacid, an antibody or antigen-binding fragment thereof, a fusion protein,an integrin antagonist, a cyclic peptide, a disintegrin, apeptidomimetic, or a small molecule. In some embodiments, the inhibitorynucleic acid is a small hairpin RNA, a small interfering RNA, anantisense, an aptamer, or a microRNA.

Inhibitory Nucleic Acids of Integrins

In some embodiments, the inhibitory nucleic acid can be an antisensenucleic acid, a ribozyme, a small interfering RNA, a small hairpin RNA,or a microRNA. Examples of aspects of these different inhibitory nucleicacids are described below.

Exemplary integrin inhibitors that are antisense nucleic acids includeATL1102 (e.g., Limmroth et al., Neurology 83(20):1780-1788, 2014; Li etal., Dig. Liver Dis. 39(6):557-565, 2007; Goto et al., Inflamm. BowelDis. 12(8):758-765, 2006).

Non-limiting examples of integrin inhibitors that are short interferingRNAs (siRNAs) are described in Wang et al., Cancer Cell Int. 16:90,2016). In some embodiments, the integrin inhibitor is a short hairpinRNA (shRNA).

Non-limiting examples of integrin inhibitors that are microRNA includemiR-124 (Cai et al., Sci. Rep. 7:40733, 2017), miR-134 (Qin et al.,Oncol. Rep. 37(2):823-830, 2017), miR-92b (Ma et al., Oncotarget8(4):6681-6690, 2007), miR-17 (Gong et al., Oncol. Rep. 36(4), 2016),miR-338 (Chen et al., Oncol. Rep. 36(3):1467-74, 2016), and miR-30a-5p(Li et al., Int. J. Oncol. 48(3):1155-1164, 2016).

In some embodiments, the integrin inhibitor can include modifiedbases/locked nucleic acids (LNAs). In some embodiments, the integrininhibitor is an aptamer (e.g., Berg et al., Mol. Ther. Nucl. Acids5:e294, 2016; and Hussain et al., Nucleic Acid Ther. 23(3):203-212,2013). Additional examples of integrin inhibitors that are inhibitorynucleic acids are described in Juliano et al., Theranostics 1:211-219,2011; Millard et al., Theranostics 1:154-188, 2011; and Teoh et al.,Curr. Mol. Med. 15:714-734, 2015. In some embodiments, the integrininhibitor is an antisense nucleic acid, e.g., alicaforsen (Yacyshyn etal., Clin. Gastroenterol. Hepatol. 5(2):215-220, 2007).

Integrin Inhibitor Antibodies

In some embodiments, the antibody is a pan-β1 antibody (e.g., OS2966(Carbonell et al., Cancer Res. 73(10):3145-3154, 2013). In someembodiments, the integrin antibody is a monoclonal antibody (e.g., 17E6(Castel et al., Eur. J. Cell. Biol. 79(7):502-512, 2000); Mitjans etal., Int. J. Cancer 87(5):716-723, 2000)). In some embodiments, themonoclonal antibody is vedolizumab (e.g., Entyvio®) or a variant thereof(Feagan et al., N. Engl. J. Med 369:699-710, 2013; Sandborn et al., N.Engl. J. Med. 369:711-721, 2013; Sands et al., Gastroenterology147:618-627, 2014; and Milch et al., Neuroimmunol. 264:123-126, 2013;Wyant et al., J. Crohns Colitis 10(12):1437-1444, 2016; and Feagan etal., Gastroenterology 142(5): S 160-5161, 2012).

In some embodiments, the antibody can be a Fab fragment of a monoclonalchimeric mouse-human antibody (e.g., abciximab (ReoPro, c7E3), Kononczuket al., Curr. Drug Targets 16(13):1429-1437, 2015; Jiang et al., Appl.Microbiol. Biotechnol. 98(1):105-114, 2014), or a variant thereof. Insome embodiments, the integrin antibody is a humanized monoclonalantibody. In some embodiments, the humanized monoclonal antibody isnatalizumab (Tysabri®) (Targan et al., Gastroenterology132(5):1672-1683, 2007; Sandborn et al., N. Engl. J. Med.353(18):1912-1925, 2005; Nakamura et al., Intern Med. 56(2):211-214,2017; Singh et al., J. Pediatr. Gastroenterol. Nutr. 62(6):863-866,2016). In some embodiments, the humanized monoclonal antibody is vitaxin(MEDI-523) or a variant thereof (Huveneers et al., Int. J. Radiat. Biol.81(11-12):743-751, 2007; Coleman et al., Circ. Res. 84(11):1268-1276,1999). In some embodiments, the humanized monoclonal antibody isetaracizumab (Abegrin®, MEDI-522, LM609) or a variant thereof (Hersey etal., Cancer 116(6):1526-1534, 2010; Delbaldo et al., Invest New Drugs26(1):35-43, 2008). In some embodiments, the humanized monoclonalantibody is CNTO95 (Intetumumab®) or a variant thereof (Jia et al.,Anticancer Drugs 24(3):237-250, 2013; Heidenreich et al., Ann. Oncol.24(2):329-336, 2013; Wu et al., J. Neurooncol. 110(1):27-36, 2012). Insome embodiments, the humanized monoclonal antibody is efalizumab(Raptiva®) or a variant thereof (Krueger et al., J. Invest. Dermatol.128(11):2615-2624, 2008; Li et al., PNAS 106(11):4349-4354, 2009;Woolacott et al., Health Technol. Assess 10:1-233, 2006). In someembodiments, the humanized monoclonal antibody is STX-100 (Stromedix®)or a variant thereof (van Aarsen et al., Cancer Res. 68:561-570, 2008;Lo et al., Am. J. Transplant. 13(12):3085-3093, 2013). In someembodiments, the humanized monoclonal antibody is 264RAD or a variantthereof (Eberlein et al., Oncogene 32(37):4406-4417, 2013).

In some embodiments, the humanized monoclonal antibody is rovelizumab ora variant thereof (Goodman et al., Trends Pharmacol. Sci 33:405-412,2012). In some embodiments, the humanized monoclonal antibody isCytolin® or a variant thereof (Rychert et al., Virology J. 10:120,2013). In some embodiments, the humanized monoclonal antibody isetrolizumab or a variant thereof (Vermeire et al., Lancet 384:309-318,2014; Rutgeerts et al., Gut 62:1122-1130, 2013; Lin et al.,Gastroenterology 146:307-309, 2014; Ludviksson et al., J. Immunol.162(8):4975-4982, 1999; Stefanich et al., Br. J. Pharmacol.162(8):1855-1870, 2011). In some embodiments, the humanized monoclonalantibody is abrilumab (AMG 181; MEDI-7183) or a variant thereof (Pan etal., Br. J. Pharmacol. 169(1): 51-68, 2013; Pan et al., Br. J. Clin.Pharmacol. 78(6): 1315-1333, 2014). In some embodiments, the humanizedmonoclonal antibody is PF-00547659 (SHP647) or a variant thereof(Vermeire et al., Gut 60(8):1068-1075, 2011; Sandborn et al.,Gastroenterology 1448(4):S-162, 2015). In some embodiments, thehumanized monoclonal antibody is SAN-300 (hAQC2) or a variant thereof(Karpusas et al., J. Mol. Biol. 327:1031-1041, 2003). In someembodiments, the humanized monoclonal antibody is DI176E6 (EMD 5257) ora variant thereof (Goodman et al., Trends Pharmacol. Sci 33:405-412,2012; and Sheridan et al., Nat. Biotech. 32:205-207, 2014).

In some embodiments, the integrin antibody is a chimeric monoclonalantibody. In some embodiments, the chimeric monoclonal antibody isvolociximab or a variant thereof (Kuwada et al., Curr. Opin. Mol. Ther.9(1):92-98, 2007; Ricart et al., Clin. Cancer Res. 14(23):7924-7929,2008; Ramakrishnan et al., J. Exp. Ther. Oncol. 5(4):273-86, 2006;Bell-McGuinn et al., Gynecol. Oncol. 121:273-279, 2011; Almokadem etal., Exp. Opin. Biol. Ther. 12:251-7, 2012).

In some embodiments, the antibody specifically binds one or more (e.g.,1, 2, 3, 4, or 5) integrin. In some embodiments, the antibodyspecifically binds an integrin dimer (e.g., MLN-00002, MLNO2 (Feagan etal., Clin. Gastroenterol. Hepatol. 6(12):1370-1377, 2008; Feagan et al.,N. Engl. J. Med. 352(24):2499-2507, 2005). In certain embodiments, theantibody comprises or consists of an antigen-binding fragment ofabciximab (Reopro™) (Straub et al., Eur. J. Cardiothorac Surg.27(4):617-621, 2005; Kim et al., Korean J. Intern. Med. 19(4):220-229,2004). In some embodiments, the integrin inhibitor is an antibody-drugconjugate (e.g., IMGN388 (Bendell et al., EJC Suppl 8(7):152, 2010).

Further examples of antibodies and antigen-binding fragments thereof aredescribed in U.S. Pat. Nos. 5,919,792; 6,214,834; 7,074,408; 6,833,373;7,655,624; 7,465,449; 9,558,899; 7,659,374; 8,562,986; 8,398,975; and8,853,149; US 2007/0117849; US 2009/0180951; US 2014/0349944; US2004/0018192; WO 11/137418; and WO 01/068586; each of which isincorporated by reference in its entirety.

Integrin Inhibitor Fusion Proteins

In some embodiments, the integrin inhibitor is a fusion protein (e.g.,an Fc fusion protein of an extracellular domain of an integrin or anintegrin receptor), a soluble receptor (e.g., the extracellular domainof an integrin or an integrin receptor), or a recombinant integrinbinding protein (e.g., an integrin ligand). See, e.g., Lode et al., PNAS96(4):1591-1596, 1999; Stephens et al., Cell Adhesion Comm. 7:377-390,2000; and US 2008/0739003; incorporated by reference herein).Non-limiting examples of fusion proteins that are integrin inhibitorsinclude Ag25426 (Proteintech).

Integrin Inhibitor Small Molecule Antagonists

In some embodiments, the integrin inhibitor is a small molecule. In someembodiments, the small molecule is a non-peptide small molecule. In someembodiments, the non-peptide small molecule is a RGD (ArgGlyAsp)-mimeticantagonist (e.g., tirofiban (Aggrastat®); Pierro et al., Eur. J.Ophthalmol. 26(4):e74-76, 2016; Guan et al., Eur. J. Pharmacol761:144-152, 2015. In some embodiments, the small molecule is α4antagonist (e.g., firategrast (Miller et al., Lancet Neurol.11(2):131-139, 2012) AJM300 (Yoshimura et al., Gastroenterology149(7):1775-1783, 2015; Takazoe et al., Gastroenterology 136(5):A-181,2009; Sugiura et al., J. Crohns Colitis 7(11):e533-542, 2013)). In someembodiments, the small molecule is α4β1 antagonist (e.g., IVL745 (Norriset al., J. Allergy Clin. Immunol. 116(4):761-767, 2005; Cox et al., Nat.Rev. Drug Discov. 9(10):804-820, 2010)), BIO-1211 (Abraham et al., Am.J. Respir. Crit. Care Med. 162:603-611, 2000; Ramroodi et al., Immunol.Invest. 44(7):694-712, 2015; Lin et al., J. Med. Chem. 42(5):920-934,1999), HMR 1031 (Diamant et al., Clin. Exp. Allergy 35(8):1080-1087,2005); valategrast (R411) (Cox et al., Nat. Rev. Drug Discov.9(10):804-820, 2010), GW559090X (Ravensberg et al., Allergy61(9):1097-1103, 2006), TR14035 (Sircar et al., Bioorg. Med. Chem.10(6):2051-2066, 2002; Cortijo et al., Br. J. Pharmacol. 147(6):661-670,2006)). In some embodiments, the small molecule is αvβ3 antagonist(e.g., L0000845704, SB273005). In some embodiments, the small moleculeis α5β1 antagonist (e.g., JSM6427). In some embodiments, the smallmolecule is GLPG0974 (Vermeire et al., J. Crohns Colitis Suppl. 1:S39,2015). In some embodiments, the small molecule is MK-0429 (Pickarksi etal., Oncol. Rep. 33(6):2737-45, 2015; Rosenthal et al., Asia Pad Clin.Oncol. 6:42-8, 2010). In some embodiments, the small molecule isJSM-6427 or a variant thereof (Zahn et al., Arch. Ophthalmol.127(10):1329-1335, 2009; Stragies et al., J. Med. Chem. 50:3786-94,2007).

In some embodiments, the small molecule integrin inhibitor can bePTG-100, which is described in, e.g., Shames et al., “Pharmakokineticsand Pharmacodynamics of the Novel Oral Peptide Therapeutic PTG-100 (α4β7Integrin Antagonist) in Normal Healthy Volunteers,” 24^(th) UnitedEuropean Gastroentrology Week, October 15-19, Vienna, Austria, 2016.

In some embodiments, the small molecule targets a β2 integrin. In someembodiments, the small molecule is SAR-118 (SAR1118) or a variantthereof (Zhong et al., ACS Med. Chem. Lett. 3(3):203-206, 2012; Suchardet al., J. Immunol. 184:3917-3926, 2010; Yandrapu et al., J. Ocul.Pharmacol. Ther. 29(2):236-248, 2013; Semba et al., Am. J. Ophthalmol.153:1050-60, 2012). In some embodiments, the small molecule isBMS-587101 or a variant thereof (Suchard et al., J. Immunol.184(7):3917-3926, 2010; Potin et al., J. Med. Chem. 49:6946-6949, 2006).See e.g., Shimaoka et al., Immunity 19(3):391-402, 2003; U.S. Pat. Nos.7,138,417; 7,928,113; 7,943,660; and 9,216,174; US 2008/0242710; and US2008/0300237.

Other exemplary integrin inhibitors include the following: SMARTanti-L-selectin Mab from PDL BioPharma Inc., which is L-Selectinantagonist, and described in WO-09706822, and Co M S, et al. “Propertiesand pharmacokinetics of two humanized antibodies specific forL-selectin”; Immunotechnology; 1999 4 253-266; both of which are herebyincorporated by reference; SEL-K2, an anti-PSGL-1 antibody, fromTetherex Pharmaceuticals Inc, which is described in Barbara Muz, et al.“Inhibition of P-Selectin and PSGL-1 Using Humanized MonoclonalAntibodies Increases the Sensitivity of Multiple Myeloma Cells toProteasome Inhibitors” American Society of Hematology Annual Meeting andExposition; 2014 56th (December 08) Abs 4758, which is herebyincorporated by reference; Vatelizumab described in I. A. Antonijevic,et al. “Safety, tolerability and pharmacodynamic characterization ofvatelizumab, a monoclonal antibody targeting very-late-antigen (VLA)-2:a randomized, double-blind, placebo-controlled phase 1 study” Abstractrelease date: Sep. 23, 2015) ECTRIMS Online Library. Oct. 9, 2015; andWO-2010095031; WO-2011104604; WO-2010052556, which are all herebyincorporated by reference; and anti-VCAM mAb, which is described inSoriano, Antonio, et al. “VCAM-1, but not ICAM-1 or MAdCAM-1,immunoblockade ameliorates DSS-induced colitis in mice.” Laboratoryinvestigation 80.10 (2000): 1541; and Gerritsen M E, et al. (1995).Activation-dependent isolation and culture of murine pulmonarymicrovascular endothelium. Microcirculation 2:151-163.

Integrin Inhibitor Cyclic Peptides

In some embodiments, the integrin inhibitor is a cyclic peptide. In someembodiments, the synthetic cyclic peptide is eptifabitide (Integrilin™),or a variant thereof. In some embodiments, the cyclic peptide comprisesa heterocyclic nucleic (e.g., a benzodiazepinone, a piperazine, abenzoazepinone, a nitroaryl, an isoxazoline, an indazole, or a phenol;Spalluto et al., Curr. Med. Chem. 12:51-70, 2005). In some embodiments,the cyclic peptide is a macrocycle (see, e.g., Halland et al., ACS Med.Chem. Lett. 5(2):193-198, 2014). In some embodiments, the peptide isALG-1001 or a variant thereof (Mathis et al., Retin. Phys. 9:70, 2012).In some embodiments, the cyclic peptide is an imidazolone-phenylalaninederivative, a heteroaryl, hetrocyclic, and aryl derivative, abicyclic-aromatic amino acid derivative, a cyclohexane-carboxylic acidderivative, a di-aryl substituted urea derivative, a multimericL-alanine derivative, a L-alanine derivative, or a pyrimidyl-sulfonamidederivative (see, e.g., U.S. Pat. Nos. 6,630,492; 6,794,506; 7,049,306;7,371,854; 7,759,387; 8,030,328; 8,129,366; 7,820,687; 8,350,010; and9,345,793).

Integrin Inhibitor Peptidomimetics

In some embodiments, the integrin inhibitor is a peptidomimetic. In someembodiments, the peptidomimetic has an integrin-ligand recognition motif(e.g., RGD, KTS, or MLD). See, e.g., Carron et al., Cancer Research58:1930-1935, 1998; Fanelli et al., Vascular Cell 6:11, 2014; and DeMarco et al., Curr. Top. Med. Chem. 16(3):343-359, 2016.

In some embodiments, the peptidomimetic is an RGD(ArgGlyAsp)-basedpeptide (U.S. Pat. No. 8,809,338, incorporated by reference in itsentirety herein). In some embodiments, the RGD-based peptide can becilengitide or a variant thereof (EMD 12974) (Mas-Moruno et al.,Anticancer Agents Med. Chem. 10:753-768, 2010; Reardon et al., FutureOncol. 7(3):339-354, 2011; Beekman et al., Clin. Genitourin Cancer4(4):299-302, 2006; SC56631 (e.g., Engleman et al., Am Soc. Clin.Invest. 99(9):2284-2292, 1997; Peng et al., Nature Chem Biol. 2:381-389,2006). In some embodiments, the peptidomimetic can be a Lys-Gly-Asp(KGD)-based peptide. In some embodiments, the peptidomimetic can bevipegitide or a variant thereof (Momic et al., Drug Design Devel.Therapy 9:291-304, 2015). In some embodiments, the peptidomimetic can bea peptide conjugated with an antimicrobial synthetic peptide. (e.g.,ACDCRGDCFC conjugated with (KLAKLAK)₂ (Ellerby et al., Nat. Med.5(9):1032-1038, 1999). See, e.g., U.S. Pat. No. 8,636,977.

Disintegrins

In some embodiments, the integrin inhibitor can be a disintegrin. Theterm “disintegrin” as used herein refers to a low molecular weightpeptide integrin inhibitor derived from a snake venom (e.g., pit vipervenom). In some embodiments, the disintegrin is a RGD(ArgGlyAsp)-, aKTS- or an MLD-based disintegrin.

Non-limiting examples of disintegrins include accutin, accurhagin-C,albolabrin, alternagin-c, barbourin, basilicin, bitisgabonin-1,bitisgabonin-2, bitistatin, cerastin, cereberin, cumanastatin 1,contortrostatin, cotiarin, crotatroxin, dendroaspin, disba-01, durissin,echistatin, EC3, elegantin, eristicophin, eristostatin, EMS11, EO4, EO5,flavoridin, flavostatin, insularin, jarastatin, jerdonin, jerdostatin,lachesin, lebein (e.g., lebein-1, lebein-2), leberagin-C, lebestatin,lutosin, molossin, obtustatin, ocellatusin, rhodocetin, rhodostomin,R-mojastin 1, salmosin, saxatilin, schistatin, tablysin-15, tergeminin,triflavin, trigramin, trimestatin, VA6, vicrostatin, viridin,viperstatin, VB7, VLO4, and VLO5, or a variant thereof. See, e.g.,Arruda Macedo et al., Curr. Protein. Pept. Sci. 16(6):532-548, 2015; Hsuet al., Sci. Rep. 6:23387, 2016; Kele et al. Curr. Protein Pept. Sci.6:532-548, 2015; Koh et al., Toxicon 59(4):497-506, 2012; Scarborough etal., J. Biol. Chem. 268:1058-1065, 1993; Kisiel et al., FEBS Lett.577:478-482, 2004; Souza et al., Arch. Biochem. Biophys. 384:341-350,2000; Eble et al., J. Biol. Chem. 278:26488-26496, 2003; Marcinkiewiczet al., J. Biol. Chem. 274:12468-12473, 1999; Calvete et al., J.Proteome Res. 6:326-336, 2007; Scibelli et al., FEMS Microbiol. Lett.247:51-57, 2005; Oliva et al., Toxicon 50:1053-1063, 2007; Minea et al.,Toxicon 59:472-486, 2012; Smith et al., FEBS Lett. 512:111-115, 2002;Tselepis et al., J. Biol. Chem. 272:21341-21348, 1997; Da Silva et al.,Tromb. Res. 123:731-739, 2009; Thibault et al., Mol. Pharmacol.58:1137-1145, 2000; Lu et al., Biochem. J. 304:818-825, 1994; Yeh etal., Biochim. Biophys. Acta. 1425:493-504, 1998; Huang et al., Exp.Hematol. 36:1704-1713, 2008; Shih et al., Matrix Biol. 32:152-159, 2013;Wang et al., Br. J. Pharmacol. 160:1338-1351, 2010; Della-Casa et al.,Toxicon 57:125-133, 2011; Sheu et al., Biochim. Biophys. Acta.1336:445-454, 1997; Fujii et al., J. Mol. Biol. 332:115-122, 2003;Bilgrami et al., J. Mol. Biol. 341:829-837, 2004; Zhou et al., Toxicon43:69-75, 2004; Scarborough et al., J. Biol. Chem. 268:1066-1073, 1993;Shebuski et al., J. Biol. Chem. 264:21550-21556, 1989; Lu et al.,Biochem. J. 304:929-936, 1994; McLane et al., Biochem. J. 301:429-436,1994; Juarez et al., Toxicon 56:1052-1058, 2010; Olfa et al., Lab.Invest. 85:1507-1516, 2005; Elbe et al., Matrix Biol. 21:547-558, 2002;Bazan-Socha et al., Biochemistry 43:1639-1647, 2004; Danen et al., Exp.Cell. Res. 238:188-196, 1998; Marcinkiewicz et al., Biochemistry38(40):13302-13309, 1999; Calvete et al., Biochem. J. 372:725-734, 2003;Swenson et al., Pathophysiol. Haemost. Thromb. 34:169-176, 2005; Kwon etal., PLoS One 8; e81165, 2013; Yang et al., Toxicon 45:661-669, 2005;Limam et al., Matrix Biol. 29:117-126, 2010; Gan et al., J. Biol. Chem.263:19827-19832, 1988; Ma et al., Thromb. Haemost. 105(6):1032-1045,2011; and U.S. Pat. No. 7,074,408, incorporated in their entiretyherein.

CXCL10 (IP-10) Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CXCL10 (IP-10) inhibitor. As usedherein “CXCL10”, “interferon gamma-induced protein 10” and “IP-10” canbe used interchangeably. CXCL10 binds to the CXCR3 receptor (e.g.,CXCR3-A or CXCR3-B). The term “CXCL10 inhibitor” refers to an agentwhich decreases the ability of CXCL10 to bind to a CXCR3 receptor (e.g.,CXCR3-A and/or CXCR3-B).

CXCL10 (IP-10) Inhibitor Antibodies

In some embodiments, the CXCL10 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment described hereinbinds specifically to CXCL10 or a CXCR3 receptor (e.g., CXCR3-A and/orCXCR3-B), or both a CXCL10 and a CXCR3 receptor (e.g., CXCR3-A and/orCXCR3-B). In some embodiments, a CXCL10 inhibitor can bind to bothCXCR3-A and CXCR3-B.

In some instances, the CXCL10 inhibitor is a monoclonal antibody (mAb)(see, e.g., WO 05/58815). For example, the CXCL10 inhibitor can beEldelumab® (MDX-1100 or BMS-936557), BMS-986184 (Bristol-Meyers Squibb),or NI-0801 (NovImmune). See, e.g., Kuhne et al., J. Immunol.178(1):5241, 2007; Sandborn et al., J. Crohns Colitis 11(7):811-819,2017; and Danese et al., Gastroenterology 147(5):981-989, 2014.Additional examples of CXCL10 inhibitors that are antibodies aredescribed in U.S. Patent Application Publication Nos. 2017/0158757,2017/0081413, 2016/0009808, 2015/0266951, 2015/0104866, 2014/0127229,2014/0065164, 2013/0216549, 2010/0330094, 2010/0322941, 2010/0077497,2010/0021463, 2009/0285835, 2009/0169561, 2008/0063646, 2005/0191293,2005/0112119, 2003/0158392, 2003/0031645, and 2002/0018776; and WO98/11218, each of which is incorporated by reference in its entirety(e.g., the description of CXCL10 inhibitors).

CXCL10 (IP-10) Inhibitor Small Molecules and Peptides

In some instances, the CXCL10 inhibitor is a small molecule. Forexample, the CXCL10 inhibitor can be ganodermycin (see, e.g., Jung etal., J. Antiobiotics 64:683-686, 2011). Additional exemplary smallmolecule CXCL10 inhibitors are described in: U.S. Patent ApplicationPublication No. 2005/0075333; U.S. Patent Application Publication No.2004/0242498; U.S. Patent Application Publication No. 2003/0069234; U.S.Patent Application Publication No. 2003/0055054; U.S. Patent ApplicationPublication No. 2002/0169159; WO 97/24325; WO 98/38167; WO 97/44329; WO98/04554; WO 98/27815; WO 98/25604; WO 98/25605; WO 98/25617; WO98/31364; Hesselgesser et al., J. Biol. Chem. 273(25):15687-15692(1998); and Howard et al., J. Med. Chem. 41(13):2184-2193 (1998).

In some examples, the CXCL10 inhibitor is a peptide antagonist of aCXCR3 receptor (e.g., as described in U.S. Patent ApplicationPublication No. 2007/0116669, 2006/0204498, and WO 98/09642). In someexamples, the CXCL10 inhibitor is a chemokine mutant or analogue, e.g.,those described in U.S. Pat. No. 5,739,103, WO 96/38559, and WO98/06751. Additional examples of CXCL10 inhibitors that are smallmolecules or peptides are known in the art.

CCL11 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CCL11 inhibitor. The term “CCL11inhibitor” refers to an agent which decreases the ability of CCL11 tobind to one or more of CCR2, CCR3, and CCR5. In some embodiments, aCCL11 inhibitor is an antibody or an antigen-binding fragment thereof.

CCL11 Inhibitor Antibodies

In some embodiments, the CCL11 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment described hereinbinds specifically to CCL11, CCR2, CCR3, or CCR5, or can specificallybind to two or more of CCL11, CCR2, CCR3, and CCR5. In some embodiments,a CCL11 inhibitor can bind to two or more of CCR2, CCR3, and CCR5.

In some examples the chemokine/chemokine receptor inhibitor isbertilimumab (Immune Pharmaceuticals), an anti-eotaxin-1 monoclonalantibody that targets CCL11, and is currently in a Phase II clinicalstudy for ulcerative colitis. Additional examples of CCL11 inhibitorsare described in U.S. Patent Application Publication Nos. 2016/0289329,2015/0086546, 2014/0342450, 2014/0178367, 2013/0344070, 2013/0071381,2011/0274696, 2011/0038871, 2010/0074886, 2009/0297502, 2009/0191192,2009/0169541, 2009/0142339, 2008/0268536, 2008/0241923, 2008/0241136,2005/0260139, 2005/0048052, 2004/0265303, 2004/0132980, 2004/0126851,2003/0165494, 2002/0150576, 2002/0150570, 2002/0051782, 2002/0051781,2002/0037285, 2002/0028436, 2002/0015700, 2002/0012664, 2017/0131282,2016/0368979, 2016/0208011, 2011/0268723, 2009/0123375, 2007/0190055,2017/0049884, 2011/0165182, 2009/0226434, 2009/0110686, 2009/0047735,2009/0028881, 2008/0107647, 2008/0107595, 2008/0015348, 2007/0274986,2007/0231327, 2007/0036796, 2007/0031408, 2006/0229336, 2003/0228306,2003/0166870, 2003/0003440, 2002/0019345, and 2001/0000241, each ofwhich is incorporated by reference in its entirety (e.g., thedescription of CCL11 inhibitors).

CCR2 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CCR2 inhibitor. As used herein “CCR2,”“CC chemokine receptor 2,” or “MCP-1” can be used interchangeably. CCL2,CCL8, and CCL16 each individually bind to CCR2. The term “CCR2inhibitor” refers to an agent which decreases the ability of CCR2 tobind to one or more (e.g., two, or three) of CCL2, CCL8, and CCL16.

In some instances, the CCR2 inhibitor is a small molecule. In someinstances, the CCR2 inhibitor is an antibody or an antigen-bindingantibody fragment. In some instances, the CCR2 inhibitor is a peptide.

CCR2 Inhibitor Antibodies

In some embodiments, the CCR2 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment described hereinbinds specifically to CCR2. In some embodiments, an antibody orantigen-binding fragment described herein binds specifically to CCL2. Insome embodiments, an antibody or antigen-binding fragment describedherein binds specifically to CCL8. In some embodiments, an antibody orantigen-binding fragment described herein binds specifically to CCL16.In some embodiments, an antibody or antigen-binding fragment describedherein binds specifically to CCR2 and one or more of (e.g., one, two, orthree) of CCL2, CCL8, and CCL16.

In some embodiments, the CCR2 inhibitor is a monoclonal antibody. Forexample, the CCR2 inhibitor can be MLN1202 (Millennium Pharmaceuticals),C775, STI-B0201, STI-B0211, STI-B0221, STI-B0232, carlumab (CNTO 888;Centocor, Inc.), or STI-B0234, or an antigen-binding fragment thereof.See also, e.g., Vergunst et al., Arthritis Rheum. 58(7):1931-1939, 2008.Additional examples of CCR2 inhibitors that are antibodies orantigen-binding antibody fragments are described in, e.g., U.S. PatentApplication Publication Nos. 2015/0086546, 2016/0272702, 2016/0289329,2016/0083482, 2015/0361167; 2014/0342450, 2014/0178367, 2013/0344070,2013/0071381, 2011/0274696, 2011/0059107, 2011/0038871, 2009/0068109,2009/0297502, 2009/0142339, 2008/0268536, 2008/0241923, 2008/0241136,2007/0128112, 2007/0116708, 2007/0111259, 2006/0246069, 2006/0039913,2005/0232923, 2005/0260139, 2005/0058639, 2004/0265303, 2004/0132980,2004/0126851, 2004/0219644, 2004/0047860, 2003/0165494, 2003/0211105,2002/0150576, 2002/0051782, 2002/0042370, and 2002/0015700; and U.S.Pat. Nos. 6,312,689, 6,084,075, 6,406,694, 6,406,865, 6,696,550,6,727,349, 7,442,775, 7,858,318, 5,859,205, 5,693,762, and 6,075,181,each of which is incorporated by reference (e.g., the description of theCCR2 inhibitors). Additional examples of CCR2 inhibitors are describedin, e.g., WO 00/05265. Additional examples of CCR2 inhibitors that areantibodies or antigen-binding antibodies fragments are described in,e.g., Loberg et al., Cancer Res. 67(19):9417, 2007.

CCR2 Inhibitor Small Molecules and Peptides

In some examples, the CCR2 inhibitor is a small molecule. For example,the CCR2 inhibitor can be elubrixin, PF-04634817, BMS-741672, or CCX872.See, e.g., U.S. Pat. No. 9,434,766; U.S. Patent Application PublicationNo. 20070021466; Deerberg et al., Org. Process Rev. Dev.20(11):1949-1966, 2016; and Morganti et al., J. Neurosci. 35(2):748-760,2015.

Additional non-limiting examples of CCR2 inhibitors that are smallmolecules include, e.g., the phenylamino substituted quaternary saltcompounds described in U.S. Patent Application Publication No.2009/0112004; the biaryl derivatives described in U.S. PatentApplication Publication No. 2009/0048238; the pyrazol derivativesdescribed in U.S. Patent Application Publication No. 2009/0029963; theheterocyclic compounds described in U.S. Patent Application PublicationNo. 2009/0023713; the imidazole derivatives described in U.S. PatentApplication Publication No. 2009/0012063; the aminopyrrolidinesdescribed in U.S. Patent Application Publication No. 2008/0176883; theheterocyclic cyclopentyl tetrahydroisoquinolones andtetrahydropyridopyridines described in U.S. Patent ApplicationPublication No. 2008/0081803; the heteroaryl sulfonamides described inU.S. Patent Application Publication No. 2010/0056509; the triazolylpyridyl benzenesulfonamides described in U.S. Patent ApplicationPublication No. 2010/0152186; the bicyclic and bridged nitrogenheterocycles described in U.S. Patent Application Publication No.2006/0074121; the fused heteroaryl pyridyl and phenylbenzenesulfonamides described in WO 09/009740; and the3-aminopyrrolidene derivatives described in WO 04/050024.

Additional non-limiting examples of CCR2 inhibitors include:N-((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naph-thyri-din-6(5H)-yl]carbonyl}cyclopentyl)-N-[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine; 3 [(3S,4R)-1-((1R,3S)-3-isopropyl-2-oxo-3-{[6-(trifluoromethyl)-2H-1,3-ben-z-oxazin-3(4H)-yl]methyl}cyclopentyl)-3-methylpiperidin-4-yl]benzoic acid; (3S,48)-N-((1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquin-olin-2(1B)-yl]carbonyl}cyclopentyl)-3-methyltetrahydro-2H-p-yran-4-aminium;3-[(3 S,4R or 3R,4 S)-1-((1R,3S)-3-Isopropyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3-(4H)-yl]carbonyl}cyclopentyl)-3-methylpiperidin-4-yl]benzoicacid; INCB3284; Eotaxin-3; PF-04178903 (Pfizer), and pharmaceuticallyacceptable salts thereof.

Additional non-limiting examples of CCR2 inhibitors include: bindarit(2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropionic acid); AZD2423(AstraZeneca); the indole describes described in U.S. Pat. Nos.7,297,696, 6,962,926, 6,737,435, and 6,569,888; the bicyclic pyrrolederivatives described in U.S. Pat. Nos. 6,441,004 and 6,479,527; theCCR2 inhibitors described in U.S. Patent Application Publications Nos.2005/0054668, 2005/0026975, 2004/0198719, and 2004/0047860, and Howardet al., Expert Opin. Ther. Patents 11(7):1147-1151 (2001).

Additional non-limiting examples of CCR2 inhibitors that are smallmolecules are described in, e.g., WO 97/24325; WO 98/38167; WO 97/44329;WO 98/04554; WO 98/27815; WO 98/25604; WO 98/25605; WO 98/25617; WO98/31364; Hesselgesser et al., J. Biol. Chem. 273(25):15687-15692, 1998;and Howard et al., J. Med. Chem. 41(13):2184-2193, 1998.

In some embodiments, the CCR2 inhibitor is a small nucleic acid, e.g.,NOX-E36 (a 40-nucleotide L-RNA oligonucleotide that is linked to a40-kDa PEG; NOXXON Pharma AG).

In some embodiments, the CCR2 inhibitor is a peptide, e.g., a dominantnegative peptide described in, e.g., Kiyota et al., Mol. Ther.17(5):803-809, 2009, and U.S. Patent Application Publication No.20070004906, or an antagonistic peptide, e.g., the antagonistic peptidesdescribed in WO 05/037305 and Jiang-Hong Gong, et al., J. Exp. Med.186:131, 1997. Additional examples of CCR2 inhibitors that are peptidesare described in, e.g., U.S. Pat. No. 5,739,103; WO 96/38559; WO98/06751; and WO 98/09642. In some embodiments, a CCR2 inhibitor is aCCR2 mutein (e.g., U.S. Patent Application Publication No.2004/0185450).

Additional examples of CCR2 inhibitors that are small molecules andpeptides are known in the art.

CCR9 Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a CCR9 inhibitor. As used herein “CCR9”or “CC chemokine receptor 9” can be used interchangeably. CCR9specifically binds to CCL25. The term “CCR9 inhibitor” refers to anagent which decreases the ability of CCR9 to bind to CCL25.

CCR9 Inhibitor Antibodies

In some embodiments, the CCR9 inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment described hereinbinds specifically to CCR9. In some embodiments, an antibody orantigen-binding fragment described herein binds specifically to CCL25.In some embodiments, an antibody or antigen-binding fragment describedherein binds specifically to both CCR9 and CCL25.

In other instances, the CCR9 inhibitor is a monoclonal antibody. Forexample, the CCR9 antibody can be 91R, see, e.g., Chamorro et al., MAbs6(4): 1000-1012, 2014. Additional non-limiting examples of CCR9inhibitors are described in, e.g., U.S. Patent Application PublicationNos. 2012/0100554, 2012/0100154, 2011/0123603, 2009/0028866, and2005/0181501.

CCR9 Inhibitor Small Molecules

In some instances, the CCR9 inhibitor is a small molecule. For example,the CCR9 inhibitor can be Traficet-EN® (also called Vercirnon, CCX282,and GSK1605786) or Tu1652 CCX507. See, e.g., Eksteen et al., IDrugs13(7):472-481, 2010; and Walters et al., Gastroenterology 144(5):S-815,2013. Additional examples of CCR9 inhibitors that are small moleculesare known in the art.

ELR Chemokine Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is an ELR chemokine inhibitor. ELRchemokines are CXC chemokines that have a glutamic acid-leucine-arginine(ELR) motif. See, e.g., Strieter et al., J. Biol. Chem. 270:27348-27357,1995. The term “ELR chemokine inhibitor” refers to an agent whichdecreases the ability of CXCR1 and/or CXCR2 to bind to one or more(e.g., two, three, four, five, six, seven, or eight) of CXCL1, CXCL2,CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, and CXCL8.

In some instances, the ELR chemokine inhibitor is a small molecule. Insome instances, the ELR chemokine inhibitor is an antibody or anantigen-binding antibody fragment.

ELR Chemokine Inhibitor Antibodies

In some embodiments, the ELR chemokine inhibitor is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment binds specificallyto CXCR1 and/or CXCR2. In some embodiments, an antibody orantigen-binding fragment described herein binds specifically to one ormore (e.g., two, three, four, five, six, seven, or eight) of: CXCL1,CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, and CXCL8 (IL-8).

An ELR chemokine inhibitor can be, e.g., a monoclonal antibody. Anon-limiting example of an ELR inhibitor is TAB-099MZ. Additionalexamples of ELR chemokine inhibitors that are antibodies orantigen-binding antibody fragments are described in, e.g., U.S. Pat. No.9,290,570; and U.S. Patent Application Publication Nos. 2004/0170628,2010/0136031, 2015/0160227, 2015/0224190, 2016/0060347, 2016/0152699,2016/0108117, 2017/0131282, 2016/0060347, 2014/0271647, 2014/0170156,2012/0164143, 2010/0254941, 2009/0130110, 2008/0118517, 2004/0208873,2003/0021790, 2002/0082396, and 2001/0006637, each of which is hereinincorporated by reference (e.g., the portions describing ELR chemokineinhibitors).

ELR Chemokine Inhibitor Small Molecules

In some instances, the ELR chemokine inhibitor is, e.g., a smallmolecule. For example, the ELR chemokine inhibitor can be, e.g.,LY-3041658 or repertaxin (Reparixin; DF 1681Y). Additional non-limitingexamples of ELR chemokine inhibitors that are small molecules aredescribed in, e.g., U.S. Patent Application Publication Nos.2007/0248594, 2006/0014794, 2004/0063709, 2004/0034229, 2003/0204085,2003/0097004, 2004/0186142, 2004/0235908, 2006/0025453, 2017/0224679,2017/0190681, 2017/0144996, and 2017/0128474, each of which areincorporated by reference (e.g., the portions describing the ELRchemokine inhibitors).

In some embodiments, the ELR chemokine inhibitor is a peptide, e.g., anyof the peptides described in U.S. Patent Application Publication Nos.2009/0270318, 2009/0118469, and 2007/0160574, 2007/0021593,2003/0077705, and 2007/0181987, each of which is incorporated byreference (e.g., the portions describing the ELR chemokine inhibitors).

Phosphodiesterase 4 (PDE4) Inhibitors

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a PDE4 inhibitor. The term “PDE4inhibitor” refers to an agent which decreases PDE4 activity in vitro orin a mammalian cell, e.g., as compared to the level of PDE4 activity inthe absence of the agent; and/or decreases the level of a PDE4 proteinin a mammalian cell contacted with the agent, e.g., as compared to thesame mammalian cell not contacted with the agent. A non-limiting exampleof PDE4 activity is the degradation of cAMP.

In some embodiments, a PDE4 inhibitor can be a small molecule (e.g., anorganic, an inorganic, or bioinorganic molecule) having a moleculeweight of less than 900 Daltons (e.g., less than 500 Daltons). In someembodiments, a PDE4 inhibitor can be an inhibitory nucleic acid.

Inhibitory Nucleic Acids of PDE4

In some embodiments, a PDE4 inhibitor can be an inhibitory nucleic acid.In some embodiments, the inhibitory nucleic acid can be an antisensenucleic acid, a ribozyme, and a small interfering RNA (siRNA).

Examples of modified nucleotides which can be used to generate anantisense nucleic acid include 5-fluorouracil, 5-bromouracil,5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine,5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can beproduced biologically using an expression vector into which a nucleicacid has been subcloned in an anti sense orientation (i.e., RNAtranscribed from the inserted nucleic acid will be of an antisenseorientation to a target nucleic acid of interest).

Another example of an inhibitory nucleic acid is a ribozyme that hasspecificity for a nucleic acid encoding a PDE4 protein (e.g.,specificity for a PDE4 mRNA, e.g., specificity for SEQ ID NO: 1, 2, 3,4, or 5). Ribozymes are catalytic RNA molecules with ribonucleaseactivity that are capable of cleaving a single-stranded nucleic acid,such as an mRNA, to which they have a complementary region. Thus,ribozymes (e.g., hammerhead ribozymes (described in Haselhoff andGerlach, Nature 334:585-591, 1988)) can be used to catalytically cleavemRNA transcripts to thereby inhibit translation of the protein encodedby the mRNA. A ribozyme having specificity for a PDE4 mRNA can bedesigned based upon the nucleotide sequence of any of the PDE4 mRNAsequences disclosed herein. For example, a derivative of a TetrahymenaL-19 IVS RNA can be constructed in which the nucleotide sequence of theactive site is complementary to the nucleotide sequence to be cleaved ina PDE4 mRNA (see, e.g., U.S. Pat. Nos. 4,987,071 and 5,116,742).Alternatively, a PDE4 mRNA can be used to select a catalytic RNA havinga specific ribonuclease activity from a pool of RNA molecules. See,e.g., Bartel et al., Science 261:1411-1418, 1993.

An inhibitor nucleic acid can also be a nucleic acid molecule that formstriple helical structures. For example, expression of a PDE4 polypeptidecan be inhibited by targeting nucleotide sequences complementary to theregulatory region of the gene encoding the PDE4 polypeptide (e.g., thepromoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb,3 kb, 4 kb, or 5 kb upstream of the transcription initiation startstate) to form triple helical structures that prevent transcription ofthe gene in target cells. See generally Helene, Anticancer Drug Des.6(6):569-84, 1991; Helene, Ann. N.Y. Acad. Sci. 660:27-36, 1992; andMaher, Bioassays 14(12):807-15, 1992.

Non-limiting examples of siRNAs targeting PDE4 are described in Takakuraet al., PLosOne 10(12):e0142981, 2015; Watanabe et al., Cell Signal27(7):1517-1524, 2015; Suzuki et al., PLos One 11(7):e0158967, 2016; Kaiet al., Mol. Ther. Nucl. Acids 6: 163-172, 2017). See, e.g., Cheng etal. Exp Ther Med 12(4): 2257-2264, 2016; Peter et al., J Immunol 178)8):4820-4831; and Lynch et al. J Biolog Chem 280: 33178-33189. Additionalexamples of PDE4 inhibitory nucleic acids are described in U.S. PatentApplication Publication Nos. 2010/0216703 and 2014/0171487, which areincorporated by reference in its entirety.

PDE4 Inhibitor Small Molecules

In some embodiments, a PDE4 inhibitor is a small molecule. Non-limitingexamples of small molecules that are PDE4 inhibitors include: Apremilast(CC-10004; CC-110004; CDC-104; Otezla®; lead selCID (2); selCID);CC-1088 (CC-1088; CC-5048; CC-801; CDC-801; lead SelCID (1)); Tetomilast(OPC-6535); KF-19514; PF-06266047; SKF-107806; PDB-093; Tolafentrine(BY-4070); TAK-648; CH-928; CH-673; CH-422; ABI-4 (18F-PF-06445974;Fluorine-18-PF-06445974); roflumilast; Roflumilast N-oxide (APTA-2217;B9302-107; BY-217; BYK-20860; Daliresp®; Dalveza; Daxas®; Libertek;Xevex; roflumist); NVP-ABE-171; BYK-321084; WAY-127093B; NCS-613;SDZ-ISQ-844; GS-5759; Ro-20-1724; Hemay-005; KCA-1490; TVX-2706;Nitraquazone; Filaminast (PDA-641; WAY-PDA-641); LASSBio-596; ASP-3258;TAS-203; AN-2889; AN-5322; AN-6414; AN-6415; Lotamilast (E-6005;RVT-501); GPD-1116; Cipamfylline (BRL-61063; HEP-688); MNP-001; MS-23;MSP-001; K-34; KF-66490; AL-38583 (cilomast); ZL-N-91; Almirall;CDP-840; GSK-356728; Cilomilast (Ariflo; SB-207499); OCID-2987; AN-2898;CBS-3595; ASP-9831 (ASP9831); E-4021 (4-Piperidinecarboxylic acid,1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]);Piclamilast (RP-73401; RPR-73401); CD-160130; GSK-256066 (256066);4AZA-PDE4; YM-393059; Revamilast (GRC-4039); AN-2728 (PF-06930164;crisaborole (Eucrisa™)); MK-0952 (MK-952); Ibudilast (AV-411; MN-166;KC-404); GP-0203; ELB-526; Theophylline (Teonova); CHF-6001 (CHF-5480);Elbimilast (AWD-12-353; ELB-353; ronomilast); AWD-12-281 (842470);OS-0217; Oglemilast (GRC-3886); R-1627; ND-1510; ND-1251; WAY-122331;GRC-3566; Tofimilast (CP-325366); BAY-61-9987; Rolipram (ME-3167;ZK-62711); MEM-1414 (R-1533); Adenosine A3 antagonists (CGH-2466);RPL-554 (RPL-565; VMX-554; VMX-565; VRP-554; trequinsin analog);CT-5357; Etazolate (EHT-0202; SQ-20009; etazolate hydrochloride);Z-15370 (Z-15370A); Org-30029; Org-20241; Arofylline (LAS-31025);Arofylline derivatives; KW-4490; HT-0712 (IPL-455903); HT-0712;IPL-455903; CT-2450; CT-2820; CT-3883; CT-5210; L-454560; L-787258;L-791943; L-826141; L-869298; MK-0359; OX-914 (BLX-028914; BLX-914;IPL-4088; IPL-4182; IPL-4722); SDZ-PDI-747; AP-0679; Sch-351591 (D-4396;Sch-365351); TA-7906 (T-2585; TA-7906); HMR-1571; Lirimilast(BAY-19-8004); Daxalipram (Mesopram; SH-636; ZK-117137); SelCIs(CC-10036; CC-10083; CC-110007; CC-110036; CC-110037; CC-110038;CC-110049; CC-110052; CC-110083; CC-11069; CC-111050; CC-13039;CC-14046; CC-17034; CC-17035; CC-17075; CC-17085; CC-18062; CC-7075);RPR-117658; AWD-12-281 (842470; AWD-12-343; GW842470X); 256066(GSK-256066; SB-207499); RPR-132294 (RPR-132703); CI-1018; CI-1044;PD-168787; PD-189659; PD-190036; PD-190749; YM-976; XT-611; Losartanderivatives; DWP-205 derivatives (DWP-205297); WAY-126120; YM-58997;CP-293321; V-11294A; CH-3697; CP-353164; Atizoram (CP-80633); D-4418;RPR-114597; IC-197; IC-246; IC-247; IC-485; IC-86518; IC-86518/IC-86521;IC-86521; CP-220629; ZL-n-91; D-22888 (AWD-12-232); GW-3600; GSK356278;TPI 1100; BPN14770; and MK-0873. See, e.g., Schafter et al. (2014)Cellular Signaling 26(9): 2016-2029); Gurney et al. (2011) Handb ExpPharmacol 204: 167-192; Spadaccini et al. (2017) Intl J Mol Sciences 18:1276; Bickston et al. (2012) Expert Opinion Invest Drugs 21:12,1845-1849; Keshavarzian et al. (2007) Expert Opinion Invest Drugs 16:9,1489-1506.

Additional examples of small molecules that are PDE4 inhibitors aredescribed in, e.g., U.S. Patent Application Publication Nos.2017/0348311, 20176/0319558, 2016/0213642, 2015/0328187, 2015/0306079,2015/0272949, 2015/0272936, 2015/0080359, 2015/0051254, 2014/0350035,2014/0148420, 2014/0121221, 2013/0252928, 2013/0237527, 2013/0225609,2012/0309726, 2012/0196867, 2012/0088743, 2012/0059031, 2012/0035143,2012/0028932, 2011/0021478, 2011/0021476, 2010/0234382, 2010/0129363,2010/0069392, 2010/0056604, 2010/0048616, 2010/0048615, 2009/0099148,2009/0093503, 2008/0287522, 2008/0255209, 2008/0255186, 2008/0221111,2007/0232637, 2007/0208181, 2007/0167489, 2006/0269600, 2006/0183764,2006/0154934, 2006/0094723, 2006/0079540, 2005/0267135, 2005/0234238,2005/0033521, 2003/0229134, 2003/0220352, 2003/0212112, 2003/0158189,2003/0069260, 2003/0050329, 2002/0058687, and 2002/0028842. Additionalexamples of small molecules that are PDE4 inhibitors are known in theart.

Additional Inhibitors

In some embodiments, the therapeutic agent suitable for use with thedevices and methods described herein is selected from a non-oral smallmolecule therapeutic, a heparin, a JAK inhibitor (e.g., PF-06700841,PF-06651600); live biotherapeutics (e.g., Neuregulin 4, NN8555), animmune modulator (e.g., KHK-4083, GSK2618960, Toralizumab), a chemokine(e.g., GSK3050002 (previously known as KANAb071), E-6011, HGS-1025), aCHST15 inhibitor (e.g., SB-012), a TLR agonist (e.g., BL-7040; EN-101;Monarsen), and combinations thereof.

Non-Oral Small Molecule Therapeutics

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a non-oral small molecule.

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a non-oral antibiotic. Antibiotics whichare not given orally include: amikacin, ampicillin sulbactam,azlocillin, aztreonam, cefazolin, cefeprime, cefoperazone, cefotaxime,cefotetan, cefoxitin, ceftaroline, ceftazidime, ceftizoxime,ceftobiprole, ceftriaxone, cephalothin, colistin, daptomycin, doripenem,ertapenem, gentamicin, imipenem, kanamycin, meropenem, mezlocillin,mupirocin, nafcillin, ofloxicin, oritovacin, piperacillin, piperacillintazobactam, polymyxin B, quinupristin dalfopristin, spectinomycin,streptomycin, teicoplanin, telavancin, ticarcillin, ticarcillinclavulanic acid, tigecycline and tobramycin.

Other exemplary non-oral small molecules for delivery using any of thedevices or methods described herein include, but are not limited to,those listed in Table 11.

TABLE 11 Non-oral small molecule therapeutics adaptable for delivery viaingestible device for the treatment of the listed diseases andconditions Existing Formulation Technologies Exemplary Therapeutic AreaDrug and Methods of Patent (Exemplary Indications) Name AdministrationLiterature [Target-based Action] Enoxaparin Intravenous; EP-00040144;Hematologic; Cardiovascular (Myocardial infarction; sodium SubcutaneousU.S. Pat. No. 04,486,420; Thromboembolism) [Low molecular weightheparin] WO-08102737 Hydroxyprogesterone Intramuscular; WO-00009186Genitourinary/sexual function caproate Solution; (Premature labor;long-acting, preterm birth prevention) Subcutaneous ; [Progesteronereceptor agonist] Sustained release Plerixafor Infusion; EP-00434385Cancer; Cardiovascular; Dermatologic; Hematologic; Intravenous; Immune;Infection (Bone marrow transplantation; Sickle Solution; cell anemia)Subcutaneous [CXCR4 chemokine antagonist; Neuroplastin inhibitor]Ferumoxytol Drug coating; WO-00061191 Cancer; Hematologic;Cardiovascular (Iron deficiency Infusion; anemia) Intravenous;Nanoparticle formulation injectable; Bortezomib Formulation WO-02059130;Hematologic; Endocrine/Metabolic; Immune; powder; Freeze WO-09613266Neurology/Psychiatric; Cancer (Acute lymphoblastic drying; Infusion;leukemia; Acute myelogenous leukemia; Chronic Intravenous; lymphocyticleukemia; Graft versus host disease; Subcutaneous Lymphoplasmacyticlymphoma; Macroglobulinemia; Mantle cell lymphoma; Multiple myeloma;Myelodysplastic syndrome; Non-Hodgkin lymphoma; Non-small-cell lungcancer) [26S proteasome complex inhibitor; Proteasome inhibitor]Pemetrexed Formulation EP-00432677; Cancer disodium powder; FreezeHU-00211941 (Mesothelioma; Metastatic bladder cancer; Metastatic drying;Infusion; non-small cell lung cancer) Intravenous [DHFR inhibitor; GARtransformylase inhibitor; Thymidylate synthase inhibitor; Transferaseinhibitor] Fulvestrant Intramuscular; EP-00138504 Cancer; Inflammatory;Genitourinary/Sexual Function; Sustained release Endocrine/Metabolic(Fallopian tube cancer; Metastatic breast cancer; Metastatic ovarycancer; Peritoneal tumor; Precocious puberty) [Estrogen receptorantagonist] Carfilzomib Formulation WO-2005105827 Cancer; Hematologic(Acute lymphoblastic leukemia; powder; Freeze Cutaneous T-cell lymphoma;Hormone refractory drying; Infusion; prostate cancer; Mantle celllymphoma; Multiple Intravenous myeloma; Neuroendocrine tumor;Non-Hodgkin lymphoma; Peripheral T-cell lymphoma; Renal cell carcinoma;Small-cell lung cancer; Solid tumor) [Proteasome inhibitor; Ubiquitininhibitor] Azacitidine Formulation U.S. Pat. No. 04,965,251 Cancer;Hematologic (Acute myelogenous leukemia; powder; Freeze Chronicmyelomonocytic leukemia; Myelodysplastic drying; syndrome) [DNAmethyltransferase inhibitor] Intravenous; Subcutaneous BendamustineFormulation WO-2005034944 Endocrine/Metabolic; Cancer (Amyloidosis;B-cell powder; Freeze lymphoma; Chronic lymphocytic leukemia; Diffusedrying; Infusion; large B-cell lymphoma; Follicle center lymphoma;Intravenous; Lymphoma; Mantle cell lymphoma; Multiple myeloma; SolutionNon-Hodgkin lymphoma) [PARP modulator] Cabazitaxel Infusion; WO-09630356Cancer (Hormone refractory prostate cancer; Intravenous; Liposarcoma;Metastatic breast cancer; Metastatic Intravesical; prostate cancer;Transitional cell carcinoma) Solution Oxaliplatin Infusion;CN-101289468; Cancer (Colon tumor; Colorectal tumor; HepatocellularIntravenous U.S. Pat. No. 04,169,846 carcinoma; Metastatic colorectalcancer; Metastatic Solution pancreas cancer; Metastatic stomach cancer;Pancreas tumor; Small intestine cancer; Stomach tumor) EribulinInfusion; WO-09965894 Cancer (Angiosarcoma; Ewing sarcoma; Liposarcoma;mesylate Intravenous; Metastatic bladder cancer; Metastatic breastcancer; Solution Rhabdomyosarcoma; Soft tissue sarcoma) DocetaxelInfusion; EP-00253738 Cancer (Breast tumor; Cancer; Endometrioidcarcinoma; Intravenous; Esophagus tumor; Head and neck tumor; HormoneSolution refractory prostate cancer; Metastatic breast cancer;Metastatic non-small cell lung cancer; Metastatic stomach cancer; Ovarytumor; Prostate tumor; Squamous cell carcinoma) Sugammadex Intravenous;WO-00140316; Neurology/Psychiatric (general anesthesia) SolutionWO-2008065142 Cefoperazone Intramuscular; U.S. Pat. No. 04,234,579Genitourinary/Sexual Function; Gastrointestinal; sodium + IntravenousInfection (Bacterial infection; Bacterial meningitis; sulbactamBacterial respiratory tract infection; Bacterial urinary sodium tractinfection; Bone and joint infection; Cholangitis; Cholecystitis;Complicated skin and skin structure infection; Endometriosis; Neisseriagonorrhoeae infection; Peritonitis; Sepsis) [Beta lactamase inhibitor]Rotigotine Drug coating; WO-02089777; Musculoskeletal;Neurology/Psychiatric (Parkinsons Patch; WO-09949852 disease; Restlesslegs syndrome) Transdermal [5-HT receptor agonist; adrenergic receptoragonist; Dopamine D1, D2, D3, D4, D5 receptor agonist] CaspofunginFormulation U.S. Pat. No. 05,792,746; Gastrointestinal; Infection(Abdominal abscess; powder; Freeze WO-09421677 Aspergillus infection;Candida infection; Fungal drying; Infusion; infection; Peritonitis)Intravenous; [1,3 beta glucan synthase inhibitor] Solution Iron sucroseIntravenous WO-2004019032 Neurology/Psychiatric; Other/Miscellaneous;injection, Hematologic (Anemia; Iron deficiency anemia) Piperacillin +Antibiotic; EP-00097446 Gastrointestinal; Genitourinary/Sexual Function;tazobactam Formulation Hematologic; Dermatologic; Cardiovascular;Infection (injectable) powder; Freeze (Abdominal abscess; Abscess;Acinetobacter infection; drying; Infusion; Appendicitis; Bacterialinfection; Bacterial pneumonia; Intravenous; Solution Bacterial skininfection; Bacterial urinary tract infection; Bacteroides fragilisinfection; Bacteroides infection; Cellulitis; Cholangitis;Cholecystitis; Cystitis; Diabetic foot ulcer; Escherichia coliinfection; Febrile neutropenia; Haemophilus influenzae infection;Klebsiella pneumoniae infection; Lower respiratory tract infection;Pelvic inflammatory disease; Peritonitis; Pseudomonas aeruginosainfection; Pyelonephritis; Sepsis; Staphylococcus aureus infection)[Beta lactamase inhibitor] Dexmedetomidine Infusion; EP-00300652Neurology/Psychiatric (Anesthesia; Delirium) Intravenous; [Alpha 2adrenoceptor agonist] Solution Dalteparin Subcutaneous WO-08001383Hematologic; Dermatologic; Cardiovascular (coronary sodium thrombosis;deep vein thrombosis; lung embolism; thromboembolism) [Factor IIaantagonist; Factor Xa antagonist; Low molecular weight heparin]Bupivacaine Liposome; EP-00280503 Neurology/Psychiatric (pain; topicalanesthesia, post- Subcutaneous; operative pain) Suspension; [Sodiumchannel inhibitor] Sustained/extended release; depot foam Imipenem +Antibiotic; EP-00048025 Dermatologic; Gastrointestinal;Genitourinary/Sexual cilastatin Infusion; Function; Cardiovascular;Infection; Respiratory; Intramuscular; Inflammatory; Musculoskeletal;Ocular Intravenous (Abscess; Acinetobacter infection; Acute bronchitis;Appendicitis; Bacterial infection; Bacterial pneumonia; Bacterialrespiratory tract infection; Bacterial skin infection; Bacterial urinarytract infection; Bacteroides fragilis infection; Bacteroides infection;Bartholinitis; Bifidobacterium infection; Bone and joint infection;Cellulitis; Cholangitis; Cholecystitis; Citrobacter infection;Clostridium infection; Complicated urinary tract infection; Cornealulcer; Cystitis; Empyema; Endocarditis; Endophthalmitis; Enterobacterinfection; Enterococcus faecalis infection; Escherichia coli infection;Female genital tract infection; Gram negative bacterium infection; Grampositive bacterium infection; Haemophilus infection; Haemophilusinfluenzae infection; Infectious arthritis; Keratitis; Klebsiellainfection; Klebsiella pneumoniae infection; Morganella infection;Osteomyelitis; Panophthalmitis; Pelvic inflammatory disease;Peritonitis; Prostatitis; Proteus infection; Providencia infection;Pseudomonas aeruginosa infection; Pyelonephritis; Sepsis; Serratiainfection; Skin ulcer; Staphylococcus aureus infection; Staphylococcusinfection; Streptococcus agalactiae infection; Streptococcus infection;Streptococcus pneumoniae infection; Streptococcus pyogenes infection)[Dehydropeptidase-1 inhibitor] Tigecycline Antibiotic; EP-00536515Dermatologic; Infection (Acinetobacter infection; Infusion; Bacterialinfection; Bacterial pneumonia; Bacterial skin Intravenous infection;Bacteroides fragilis infection; Bacteroides infection; Citrobacterinfection; Clostridiaceae infection; Clostridium infection; Enterobacterinfection; Enterococcus faecalis infection; Escherichia coli infection;Haemophilus influenzae infection; Klebsiella infection; Klebsiellapneumoniae infection; Legionella pneumophila infection; MRSA infection;Staphylococcus aureus infection; Streptococcus agalactiae infection;Streptococcus infection; Streptococcus pneumoniae infection;Streptococcus pyogenes infection) Meropenem Antibiotic; EP-00126587Gastrointestinal; Infection; Respiratory (Appendicitis; Infusion;Bacterial infection; Bacterial meningitis; Bacterial Intravenouspneumonia; Bacterial respiratory tract infection; Bacterial skininfection; Bacterial urinary tract infection; Bacteroides fragilisinfection; Bacteroides infection; Bacteroides thetaiotaomicroninfection; Complicated skin and skin structure infection; Complicatedurinary tract infection; Cystic fibrosis; Enterococcus faecalisinfection; Escherichia coli infection; Haemophilus influenzae infection;Klebsiella pneumoniae infection; Neisseria meningitidis meningitis;Peptostreptococcus infection; Peritonitis; Pneumonia; Proteus mirabilisinfection; Pseudomonas aemginosa infection; Staphylococcus aureusinfection; Streptococcus agalactiae infection; Streptococcus infection;Streptococcus pneumoniae infection; Streptococcus pyogenes infection;viridans group Streptococcus infection) [Penicillin binding proteininhibitor] Ceftaroline Antibiotic; WO-09932497 Bacterial pneumonia;Bacterial skin infection; fosamil Formulation Complicated skin and skinstructure infection; powder; Infusion; Escherichia coli infection;Haemophilus influenzae Intravenous; infection; Klebsiella infection;Klebsiella pneumoniae Prodrug Solution infection; MRSA infection;Osteomyelitis; Staphylococcus aureus infection; Streptococcus agalactiaeinfection; Streptococcus pneumoniae infection; Streptococcus pyogenesinfection [Penicillin binding protein 2X inhibitor] GemcitabineFormulation CN-104650169; Cancer (Bladder tumor; Hepatobiliary systemtumor; powder; Freeze EP-00122707; Lymphoma; Metastatic bladder cancer;Metastatic breast drying; Infusion; KR-00858842 cancer; Metastaticnon-small cell lung cancer; Intravenous Metastatic ovary cancer;Metastatic pancreas cancer; Ovary tumor)

Heparins

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is a heparin. In some embodiments, theheparin is a low molecular weight heparin.

An exemplary heparin is dalteparin. Dalteparin is a low molecular weightheparin. Like other low molecular weight heparins, dalteparin is usedfor prophylaxis or treatment of deep vein thrombosis, pulmonaryembolism, venous thromboembolism, unstable angina, and non-Q-wavemyocardial infarction.

Dalteparin is delivered as an SC injection of 2500-18000 units once ortwice daily, depending on the reason for treatment. It is available insingle-dose vials, multi-dose vials, and pre-filled syringes forself-administration by the patient. The maximum concentration incurrently available formulations is 25,000 units/mL, and manyformulations contain only water and HCl/NaOH for pH adjustment. Thebioavailability is approximately 87% by SC injection, the half-life isapproximately 3-5 hours, and it is primarily eliminated by the kidneys.Dalteparin is stable at room temperature and studies have demonstrated30 days stability in commercial off-the-shelf syringes.

The primary risk of dalteparin overdose is uncontrolled hemorrhage atthe site of injection. There are few cases of dalteparin overdose in theliterature but, in most cases, the patients were discharged afterobservation without any intervention. One case describesself-administration of 360,000 units of dalteparin that was successfullymanaged with medical observation followed by discharge from the hospitalwith no notable sequelae. In the case of overdose, the action ofdalteparin may be partially reversed by the administration of protaminesulphate.

Dalteparin is a suitable therapeutic for delivery via ingestible deviceas described herein. It is currently available as a liquid, administeredby self-injection, and, because adverse injection site reactions are notuncommon, patients may readily adopt an alternative dosage form. Theprimary method of elimination is renal so first-pass through the livershould not present an obstacle to using the DDS. Lastly, the probabilityof acute reactions to overdose is low which, theoretically, could allowan increase in dose to compensate for lower bioavailability than SCinjection. Dalteparin dose is normally specified as a single value basedon the condition being treated and the weight range of the patient. Eachweight range can span 10-15 kg, suggesting that precise dosing is notcritical to achieving therapeutic effect.

Immune Modulators

In some embodiments, the therapeutic suitable for use with the devicesand methods described herein is an immune modulator. As used herein, an“immune modulator” or “immune modulatory agent” is an agent thatstimulates or suppresses the immune system and can help the body fightcancer, infection, or other diseases. The immune modulator can be atherapeutic agent that decreases the activation of an immune cell (e.g.,a T cell, e.g., memory T cell), decreases the secretion or expression ofa pro-inflammatory cytokine, decreases the recruitment or migration ofT-lymphocytes (e.g., memory T lymphocytes), and/or increases thesecretion or expression of an anti-inflammatory cytokine.

In some embodiments, an immune modulator is an antibody orantigen-binding fragment, a nucleic acid (e.g., inhibitory nucleicacid), a small molecule, or a live biotherapeutic, such as a probiotic.In some embodiments, the immune modulator is a herapeutic agent used forthe treatment of inflammatory bowel disease (IBD), for example, Crohn'sDisease or Ulcerative Colitis (UC). Non-limiting immune modulators thatare useful for treating or preventing inflammatory bowel disease includesubstances that suppress cytokine production, down-regulate or suppressself-antigen expression, or mask MHC antigens.

Non-limiting examples of immune modulators include, without limitation:CHST15 inhibitors (e.g., STNM01); IL-6 receptor inhibitors (e.g.,tocilizumab); IL-12/IL-23 inhibitors (e.g., ustekinumab and brazikumab);integrin inhibitors (e.g., vedolizumab and natalizumab); JAK inhibitors(e.g., tofacitinib); SMAD7 inhibitors (e.g., Mongersen); IL-13inhibitors; IL-1 receptor inhibitors; TLR agonists (e.g., Kappaproct);stem cells (e.g., Cx601); 2-amino-6-aryl-5-substituted pyrimidines (seeU.S. Pat. No. 4,665,077); nonsteroidal anti-inflammatory drugs (NSAIDs);ganciclovir; tacrolimus; glucocorticoids such as Cortisol oraldosterone; anti-inflammatory agents such as a cyclooxygenaseinhibitor; a 5-lipoxygenase inhibitor; or a leukotriene receptorantagonist; purine antagonists such as azathioprine or mycophenolatemofetil (MMF); NN-9499; alkylating agents such as cyclophosphamide;bromocryptine; danazol; dapsone; glutaraldehyde (which masks the MHCantigens, as described in U.S. Pat. No. 4,120,649); anti-idiotypicantibodies for MHC antigens and MHC fragments; cyclosporine;6-mercaptopurine; steroids such as corticosteroids orglucocorticosteroids or glucocorticoid analogs, e.g., prednisone,methylprednisolone, including SOLU-MEDROL®, methylprednisolone sodiumsuccinate, and dexamethasone; dihydrofolate reductase inhibitors such asmethotrexate (oral or subcutaneous); anti-malarial agents such aschloroquine and hydroxychloroquine; sulfasalazine; leflunomide; cytokineor cytokine receptor antibodies or antagonists includinganti-interferon-alpha, -beta, or -gamma antibodies, anti-tumor necrosisfactor (TNF)-alpha antibodies (infliximab (REMICADE®) or adalimumab),anti-TNF-alpha immunoadhesin (etanercept), anti-TNF-beta antibodies,anti-interleukin-2 (IL-2) antibodies and anti-IL-2 receptor antibodies,and anti-interleukin-6 (IL-6) receptor antibodies and antagonists;anti-LFA-1 antibodies, including anti-CD1 la and anti-CD18 antibodies;anti-L3T4 antibodies; heterologous anti-lymphocyte globulin; pan-Tantibodies, anti-CD3 or anti-CD4/CD4a antibodies; soluble peptidecontaining a LFA-3 binding domain (WO 90/08187 published Jul. 26, 1990);streptokinase; transforming growth factor-beta (TGF-beta);streptodomase; RNA or DNA from the host; FK506; RS-61443; chlorambucil;deoxyspergualin; rapamycin; T-cell receptor (Cohen et al., U.S. Pat. No.5,114,721); T-cell receptor fragments (Offner et al., Science,251:430-432 (1991); WO 90/11294; Ianeway, Nature, 341:482 (1989); and WO91/01133); BAFF antagonists such as BAFF or BR3 antibodies orimmunoadhesins and zTNF4 antagonists (for review, see Mackay and Mackay,Trends Immunol., 23:113-5 (2002)); biologic agents that interfere with Tcell helper signals, such as anti-CD40 receptor or anti-CD40 ligand (CD154), including blocking antibodies to CD40-CD40 ligand (e.g., Durie etal., Science, 261:1328-30 (1993); Mohan et al., J. Immunol., 154:1470-80(1995)) and CTLA4-Ig (Finck et al., Science, 265:1225-7 (1994));CD40/CD40L inhibitors; CD3 inhibitors; CD14 inhibitors; CD20 inhibitors;CD25 inhibitors; CD28 inhibitors; CD49 inhibitors; CD89 inhibitors; andT-cell receptor antibodies (EP 340,109) such as T10B9. Non-limitingexamples of agents also include the following: budesonide; epidermalgrowth factor; aminosalicylates; metronidazole; mesalamine; olsalazine;balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptorantagonists; anti-IL-1 monoclonal antibodies; growth factors; elastaseinhibitors; pyridinylimidazole compounds; TNF antagonists; IL-4, IL-10,IL-13 and/or TGFβ cytokines or agonists thereof (e.g., agonistantibodies); IL-11; glucuronide- or dextran-conjugated prodrugs ofprednisolone, dexamethasone or budesonide; ICAM-I antisensephosphorothioate oligodeoxynucleotides (ISIS 2302; Isis Pharmaceuticals,Inc.); soluble complement receptor 1 (TPlO; T Cell Sciences, Inc.);slow-release mesalazine; antagonists of platelet activating factor(PAF); ciprofloxacin; and lignocaine.

Non-limiting examples of immune modulators that are useful for treatingulcerative colitis include sulfasalazine and relatedsalicylate-containing drugs for mild cases and corticosteroid drugs forsevere cases. Non-limiting examples of immune modulators that are usefulfor treating a liver disease or disorder (e.g., liver fibrosis or NASH)include: elafibranor (GFT 505; Genfit Corp.), obeticholic acid (OCA;Intercept Pharmaceuticals, Inc.), cenicriviroc (CVC; Allergan plc),selonsertib (formerly GS-4997; Gilead Sciences, Inc.), an anti-LOXL2antibody (simtuzumab (formerly GS 6624; Gilead Sciences, Inc.)), GS-9450(Gilead Sciences, Inc.), GS-9674 (Gilead Sciences, Inc.), GS-0976(formerly NDI-010976; Gilead Sciences, Inc.), Emricasan (ConatusPharmaceuticals, Inc.), Arachidyl-amido cholanoic acid (Aramchol™;Galmed Pharmaceuticals Ltd.), AKN-083 (Allergan plc (Akarna TherapeuticsLtd.)), TGFTX4 (Genfit Corp.), TGFTX5 (Genfit Corp.), TGFTX1 (GenfitCorp.), a RoRK agonist (e.g., LYC-55716; Lycera Corp.), an ileal bileacid transporter (iBAT) inhibitor (e.g., elobixibat, Albireo Pharma,Inc.; GSK2330672, GlaxoSmithKline plc; and A4250; Albireo Pharma, Inc.),stem cells, a CCR2 inhibitor, bardoxolone methyl (Reata Pharmaceuticals,Inc.), a bone morphogenetic protein-7 (BMP-7) mimetic (e.g., THR-123(see, e.g., Sugimoto et al. (2012) Nature Medicine 18: 396-404)), ananti-TGF-β antibody (e.g., fresolimumab; see also U.S. Pat. Nos.7,527,791 and 8,383,780, incorporated herein by reference), pirfenidone(Esbriet®, Genentech USA Inc.), an anti-integrin αvβ6 antibody, ananti-connective tissue growth factor (CTGF) antibody (e.g., pamrevlumab;FibroGen Inc.), pentoxifylline, vascular endothelial growth factor(VEGF), a renin angiotensin aldosterone system (RAAS) inhibitor (e.g., arennin inhibitor (e.g. pepstatin, CGP2928, aliskiren), or an ACEinhibitor (e.g., captopril, zofenopril, enalapril, ramipril, quinapril,perindopril, lisinopril, benazepril, imidapril, fosinopril, andtrandolapril)), thrombospondin, a statin, bardoxolone, a PDE5 inhibitor(e.g., sidenafil, vardenafil, and tadalafil), a NADPH oxidase-1 (NOX1)inhibitor (see, e.g., U.S. Publication No. 2011/0178082, incorporatedherein by reference), a NADPH oxidase-4 (NOX4) inhibitor (see, e.g.,U.S. Publication No. 2014/0323500, incorporated herein by reference), anETA antagonist (e.g., sitaxentan, ambrisentan, atrasentan, BQ-123, andzibotentan), nintedanib (Boehringer Ingelheim), INT-767 (InterceptPharmaceuticals, Inc.), VBY-376 (Virobay Inc.), PF-04634817 (Pfizer),EXC 001 (Pfizer), GM-CT-01 (Galectin Therapeutics), GCS-100 (La JollaPharmaceuticals), hepatocyte growth factor mimetic (Refanalin®; AngionBiomedica), SAR156597 (Sanofi), tralokinumab (AstraZeneca), pomalidomide(Celgene), STX-100 (Biogen IDEC), CC-930 (Celgene), anti-miR-21 (RegulusTherapeutics), PRM-151 (Promedior), BOT191 (BiOrion), Palomid 529(Paloma Pharamaceuticals), IMD1041 (IMMD, Japan), serelaxin (Novartis),PEG-relaxin (Ambrx and Bristol-Myers Squibb), ANG-4011 (AngionBiomedica), FT011 (Fibrotech Therapeutics), pirfenidone (InterMune),F351 (pirfenidone derivative (GNI Pharma), vitamin E (e.g., tocotrienol(alpha, beta, gamma, and delta) and tocopherol (alpha, beta, gamma, anddelta)), pentoxifylline, an insulin sensitizer (e.g., rosiglitazone andpioglitazone), cathepsin B inhibitor R-3020, etanercept and biosimilarsthereof, peptides that block the activation of Fas (see, e.g.,International Publication No. WO 2005/117940, incorporated herein byreference), caspase inhibitor VX-166, caspase inhibitor Z-VAD-fmk,fasudil, belnacasan (VX-765), and pralnacasan (VX-740).

In some embodiments, the immune modulator is an anti-inflammatory agent.Examples of anti-inflammatory agents include, but are not limited to,IL-12/IL-23 inhibitors, TNFα inhibitors, IL-6 receptor inhibitors,immune modulatory agents (e.g., CD40/CD40L inhibitors), IL-1 inhibitors,IL-13 inhibitors, IL-10 receptor agonists, chemokine/chemokine receptorinhibitors, integrin inhibitors, and S1P modulators.

In some embodiments, the immune modulator is an integrin inhibitor.Examples of integrin inhibitors include, but are not limited to, β7(beta-7) integrin inhibitors, such as α4β7 (alpha4beta7) integrininhibitors.

In some embodiments, the immune modulator is a PDE4 inhibitor.

In some embodiments of any of the devices or methods described herein,the therapeutic is an immune modulator. In some embodiments of any ofthe devices or methods described herein, the immune modulator is anIL-12/IL-23 inhibitor, a TNFα inhibitor, a CD40/CD40L inhibitor, ananti-integrin, or an IL-1 inhibitor. In some embodiments, thetherapeutic is an immune modulator for use in a method of treating aninflammatory disease or condition that arises in a tissue originatingfrom the endoderm in a subject, where the method includes orallyadministering to the subject an ingestible device loaded with the immunemodulator, wherein the immune modulator is released by the device intothe submucosa and/or the mucosa (e.g., into the lamina propria) of thegastrointestinal tract of the subject.

Pharmaceutical Formulations

Agents such as antibodies and other therapeutic proteins and the othertherapeutic agents disclosed herein can be delivered using the devicesand methods described herein, including an ingestible device asdisclosed herein. The therapeutic agents can be incorporated intopharmaceutical formulations, which can be loaded into a device forrelease and delivery to a subject, or more particularly, for delivery ofthe formulation and/or antibody or therapeutic protein or agent to thegastrointestinal tract of a subject. In some embodiments, theformulation is delivered to the tissue of the GI tract. In someembodiments, the formulation is delivered onto or into tissue of the GItract, e.g., the mucus, mucosa or submucosa of the GI tract. In someembodiments, the formulations are fluid. In some embodiments, the fluidis a solution or a suspension. In some embodiments, the formulation is aliquid, but can be semi-solid, or solid formulations that are laterconverted to a liquid formulation. The formulations can comprise theagent and a physiologically acceptable carrier. Some formulations, whichmay be commercially or otherwise available for IV or subcutaneousdelivery, and which may be available in pre-loaded syringes or pens, mayalternatively be incorporated or loaded into a device, such as aningestible device, as disclosed herein, for release and topical deliveryof the formulation and/or antibody or therapeutic protein to thegastrointestinal tract of a subject.

In some embodiments, the therapeutic agent is formulated as a solution(e.g., an aqueous solution formulation) or a suspension or dispersion.In some embodiments, the formulation contains an antibody. Formulationscan be prepared, for example, by incorporating an antibody in therequired amount in an appropriate solvent with at least one, or acombination of, ingredients described herein. Generally, dispersions canbe prepared by incorporating an antibody into a vehicle that contains abasic dispersion medium and/or other ingredients. In some embodiments,proper fluidity of a formulation is maintained using an appropriatecoating, by the maintenance of the required particle size in the case ofdispersion, and/or by the use of surfactants. Prolonged absorption ofcompositions can be brought about by including in the composition anagent that delays absorption. In some embodiments, formulations furthercomprise one or more additional excipients to enhance performance, suchas tissue or mucosa permeation enhancement, disruption of tightepithelial junctions, absorption and/or stability. Excipients that canbe incorporated to enhance absorption by the GI tract and/or at thedisease site within the GI tract include, for example, bile salts,chelators, surfactants, anti-oxidants, fatty acids and derivativesthereof, cationic polymers, anionic polymers, and acylcarnitines.

In some embodiments, the formulation contains a high concentration ofthe therapeutic agent (e.g., about 50 mg/mL, about 100 mg/mL or about150 mg/mL or greater).

In some embodiments, the formulation suitable for use with the devicesand methods described herein optionally includes a topical anestheticagent. Thus, in some embodiments, the formulation includes an additionalagent, for example, an anesthetic agent in an amount effective tomitigate pain experienced on delivery of the drug. Examples ofanesthetic agents include, but are not limited to, ambucaine, amolanone,amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine,bupivacaine, butacaine, butamben, butanilicaine, butethamine,butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine,cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodon,dicyclomine, ecgonidine, ecgonine, ethyl chloride, etidocaine,beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine,hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate,levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methylchloride, myrtecaine, naepaine, octocaine, orthocaine, oxethazaine,parethoxycaine, phenacaine, phenol, piperocaine, piridocaine,polidocanol, pramoxine, prilocaine, procaine, propanocaine,proparacaine, propipocaine propoxycaine, pseudococaine, pyrrocaine,ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, andzolamine; and pharmaceutically acceptable salts thereof.

Formulations Containing Insulin

In some embodiments, the pharmaceutical preparation or formulation thatcan be used in the described methods and device contains insulin. Asused herein, the term “insulin” includes animal-derived insulin (such asa bovine, pig, or bovine-pig insulin, for example, as obtained from abovine or pig pancreas), native human insulin, and recombinant humaninsulin. The formulation can be a liquid, semi-solid, or solid. In someembodiments, the formulation contains the insulin and a physiologicallyacceptable carrier.

In some embodiments, the insulin preparation is provided at aconcentration of about 40 units/mL to about 500 units/mL (U-40 toU-500). In some embodiments, the insulin is provided at a concentrationof about 100 units/mL (U-100). In other embodiments, the insulin isprovided at a concentration of about 300 units/mL (U-300). In yet otherembodiments, the insulin is provided at a concentration of about 500units/mL (U-500). In yet another embodiment, there is provided aninsulin preparation containing about 40 units/mL (U-40).

In some embodiments, the insulin preparation is an excipient-freeinsulin.

In other embodiments, the insulin preparation contains one or moreexcipients. In some embodiments, the insulin preparation is an aqueousformulation comprising the insulin, an aqueous medium, and one or moreexcipients. In some embodiments, the aqueous medium is water, such aswater for injection (WFI), a buffer or a pH-adjusted water. In someembodiments, the buffer is a phosphate buffer. In some embodiments, thewater (e.g., the WFI) or the final formulation pH is adjusted to aneutral pH, for example, a pH of about 6.5 to about 8, about pH 6.8 toabout 7.8, about pH 7 to about pH 7.8, about pH 7, or more particularly,about pH 7.3 or about 7.4. A mineral acid or base can be used to adjustthe pH. In some embodiments, the mineral acid or base is selected fromhydrochloric acid (e.g., about 1N to about 2N) and sodium hydroxide(e.g., about 1N to about 2N).

In some embodiments, the one or more excipients is a preservative. Insome embodiments, the preservative is a phenolic excipient, such asphenol, m-cresol or a combination thereof.

In some embodiments, the one or more excipients is a salt or bufferingagent. In some embodiments, the salt or buffering agent is tromethamine(tris(hydroxymethyl)aminomethane), sodium chloride, or a combinationthereof. In some embodiments, the salt is zinc chloride.

In some embodiments, the one or more excipients is a surfactant. In someembodiments, the surfactant is a non-ionic surfactant. In someembodiments, the non-ionic surfactant is a polysorbate, such aspolysorbate 20, 40, 60 or 80. In some embodiments, the surfactant is apoloxamer, such as 101, 105, 108, 122, 123, 124, 181, 182, 183, 184,185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331,333, 334, 335, 338, 401, 402, 403, and/or 407.

In some embodiments, the one or more excipients is at least onestabilizing agent. In some embodiments, the stabilizing agent is atonicity stabilizer. In some embodiments, the stabilizing agent inhibitsinsulin aggregation. In some embodiments, an excipient provides one ormore functions in the formulation, for example, to provide bothsterility and stabilization from aggregation. In some embodiments, thestabilizing agent is albumin, serum (e.g., a patient's serum), or blood(e.g., a patient's blood). In some embodiments, the one or morestabilizing agents is glycerol (glycerin), a phenolic excipient, and/ora source of zinc ions, such as zinc chloride and/or zinc oxide.

In some embodiments, the formulation is a zinc-free or low zincformulation, for example, as described in U.S. Pat. No. 7,205,276B2, theentire content of which is hereby incorporated by reference in itsentirety.

In some embodiments, the at least one stabilizing agent is a phenolicexcipient. In some embodiments, the phenolic excipient is incorporatedinto the formulation in order to stabilize the insulin molecule, forexample, in a hexameric form to avoid aggregation, and/or to maintainsterility of the solution. In some embodiments, the phenolic excipientis phenol, meta-cresol, or a combination thereof. In some embodiments,the phenolic excipient is present at a concentration of about 25-35millimolar, or more particularly, about 29-32 millimolar, or about 2.5to 3.5 mg/mL, or more particularly, about 2.7 to 3.2 mg/mL. (SeeToxicology Reports, V2:194-202 (2015)).

In some embodiments, the formulation does not contain a phenolicexcipient.

In some embodiments, the insulin formulation is an aqueous solutioncomprising the insulin, an aqueous medium, glycerol, and one or moreagents selected from a phenolic excipient a source of zinc ions, and/ora surfactant.

In some embodiments, the formulation is an aqueous solution comprisingan insulin, an aqueous medium, glycerol, a phenolic excipient and asource of zinc ions. In some embodiments, the phenolic excipient isphenol or m-cresol. In a further embodiment, the phenolic excipient ism-cresol. In some embodiments, the source of zinc ions is zinc chloride.In some embodiments the aqueous medium is water for injection (WFI). Inother embodiments, the aqueous medium is a buffer or pH-adjusted water.In some embodiments, the formulation pH is adjusted to a neutral pH 7,or more particularly, to 7.4. In some embodiments, the formulation is anaqueous solution containing insulin, glycerol, metacresol, zinc chlorideand water for injection, which may be pH adjusted. In some particularembodiments, the formulation is an aqueous solution containing insulin(e.g., 100 units/mL), glycerol (16 mg/mL), metacresol (3 mg/mL), zincchloride (approximately 7 mcg/mL) and water for injection, and the pH isadjusted to 7.4 (for example, using hydrochloric acid 2N or sodiumhydroxide 2N). In a more particular embodiment, the insulin isrecombinant human insulin. In an even more particular embodiment, theformulation is Novolin® R or a generic equivalent thereof, which may becommercially or otherwise available, for example, for IV or subcutaneousdelivery.

In some embodiments, the formulation is an aqueous solution containingan insulin (e.g., insulin glulisine), an aqueous medium, a phenolicexcipient, a surfactant, and one or more salts and/or buffering agents.In some embodiments, the phenolic excipient is phenol or m-cresol. In afurther embodiment, the phenolic excipient is m-cresol. In someembodiments, the surfactant is polysorbate 20 or polysorbate 80. In someembodiments, the surfactant is polysorbate 20. In some embodiments theaqueous medium is water for injection (WFI). In other embodiments, theaqueous medium is a buffer or pH-adjusted water. In some embodiments,the formulation pH is adjusted to a neutral pH 7, or more particularly,to 7.3. In some embodiments, the aqueous medium further comprises sodiumchloride and/or trimethylamine. In some particular embodiments, theformulation is an aqueous solution containing insulin glulisine,meta-cresol, tromethamine, sodium chloride, polysorbate 20, and waterfor injection, which may be pH adjusted. In some particular embodiments,the formulation is an aqueous solution containing insulin glulisine(e.g., 100 units/mL), meta-cresol (3.15 mg/mL), tromethamine (6 mg/mL),5 mg sodium chloride (5 mg/mL), polysorbate 20 (0.01 mg/mL), and waterfor injection, wherein the pH is adjusted by addition of aqueoussolutions of hydrochloric acid and/or sodium hydroxide. In an even moreparticular embodiment, the formulation is APIDRA or a generic equivalentthereof, which may be commercially or otherwise available, for example,for IV or subcutaneous delivery.

In some embodiments, the formulation is an aqueous solution containinginsulin, an aqueous medium, glycerol, a phenolic excipient, asurfactant, a source of zinc ions, and one or more salts and/orbuffering agents. In some embodiments, the surfactant is a polysorbateor a poloxamer. In a further embodiment, the surfactant is poloxamer171. In some embodiments, the phenolic excipient is phenol or m-cresol.In a further embodiment, the phenolic excipient is phenol. In someembodiments, the source of zinc ions is zinc chloride. In someembodiments, the salt or buffering agent is trometamol or a combinationthereof. In some embodiments, the aqueous medium is pH-adjusted waterfor injections. In some embodiments, the formulation is an aqueoussolution containing insulin (e.g., 100 units/mL), phenol, zinc chloride,trometamol, poloxamer 171, glycerol, hydrochloric acid (for pHadjustment), and water for injections. In a more particular embodiment,the formulation is Insuman Infusat or a generic equivalent thereof,which may be commercially or otherwise available, for example, for IV orsubcutaneous delivery.

In some embodiments, the formulation is an aqueous solution containingan insulin (e.g., insulin lispro), an aqueous medium, glycerin, aphenolic excipient, a source of zinc ions, and one or more salts and/orbuffering agents. In some embodiments, the phenolic excipient is phenolor m-cresol. In a further embodiment, the phenolic excipient ism-cresol, which may contain trace amounts of phenol. In someembodiments, the source of zinc ions is zinc oxide. In some embodiments,the salt or buffering agent is a phosphate buffer, such has dibasicsodium phosphate. In some embodiments, the aqueous medium is an aqueousbuffer containing the dibasic sodium phosphate and water for injections.In some embodiments, the formulation is an aqueous solution containinginsulin or insulin lispro (e.g., 100 units/mL), glycerin, m-cresol(which may contain trace phenol), zinc oxide, sodium phosphate dibasicand WFI, which may be pH adjusted, for example, to a pH of between aboutpH 7.0 and 7.8. In a more particular embodiment, the formulationcontains insulin lispro (100 units/mL), glycerin (16 mg/mL), dibasicsodium phosphate (1.88 mg/mL), 3.15 mg meta-cresol (3.15 mg/mL), zincoxide content adjusted to provide 0.0197 mg/mL zinc ion, trace amountsof phenol, and Water for Injection, such that the final formulationsolution has a pH of 7.0 to 7.8, which can be achieved by addition ofaqueous solutions of hydrochloric acid 10% and/or sodium hydroxide 10%.In an even more particular embodiment, the formulation is HUMALOG or ageneric equivalent thereof, which may be commercially or otherwiseavailable, for example, for IV or subcutaneous delivery.

In some embodiments, the formulation is an aqueous solution containingan insulin, an aqueous medium, glycerol, a phenolic excipient, a sourceof zinc ions, and one or more salts and/or buffering agents. In someembodiments, the phenolic excipient is phenol, m-cresol, or acombination thereof. In a further embodiment, the phenolic excipient isphenol and m-cresol. In some embodiments, the source of zinc ions iszinc chloride. In some embodiments, the salt and/or buffering agent issodium chloride and a phosphate buffer, such has disodium phosphatedihydrate. In some embodiments, the aqueous medium is an aqueous buffercontaining the sodium chloride, the disodium phosphate dihydrate andwater for injections. In some embodiments, the formulation is an aqueoussolution containing insulin (e.g., 100 units/mL), glycerol, phenol,m-cresol, zinc chloride, sodium chloride, disodium phosphate dihydrate,water for injections, and hydrochloric acid and/or sodium hydroxide (forpH adjustment). In a more particular embodiment, the formulation isNovoRapid or a generic equivalent thereof, which may be commercially orotherwise available, for example, for IV or subcutaneous delivery.

In some embodiments, the formulation is an aqueous solution containingan insulin, an aqueous medium, glycerin, a phenolic excipient, and asource of zinc ions. In some embodiments, the phenolic excipient isphenol or m-cresol. In a further embodiment, the phenolic excipient ism-cresol. In some embodiments, the source of zinc ions is zinc oxide. Insome embodiments, the aqueous medium is pH-adjusted water forinjections. In some embodiments, the formulation is an aqueous solutioncontaining insulin (e.g., 500 units/mL), glycerin, m-cresol, zinc oxide,water for injections, and hydrochloric acid and/or sodium hydroxide (forpH adjustment). In a more particular embodiment, the formulation is anaqueous solution containing insulin (500 units/mL), glycerin (16 mg/mL),m-cresol (2.5 mg/mL), zinc oxide (to supplement endogenous zinc toobtain a total zinc content of 0.017 mg/100 units), water forinjections, and hydrochloric acid and/or sodium hydroxide (for pHadjustment). In an even more particular embodiment, the formulation isHUMULIN R U-500 or a generic equivalent thereof, which may becommercially or otherwise available, for example, for IV or subcutaneousdelivery.

In some embodiments, the insulin is a commercially available insulin orgeneric formulation thereof (see Donner T. Insulin—Pharmacology,Therapeutic Regimens And Principles Of Intensive Insulin Therapy.[Updated 2015 Oct. 12]. In: De Groot L J, Chrousos G, Dungan K, et al.,editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.;2000. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278938/),the entire content of which is hereby incorporated by reference in itsentirety). Examples of commercially available insulins include, but arenot limited to, rapid-acting insulins such as insulin lispro (Humalog®,Lilly), insulin aspart (NovoLog®, Novo Nordisk), insulin glulisine(Apidra®, Sanofi-Aventis), and technosphere insulin (Afrezza®);short-acting insulins such as regular human insulin (Humulin® R, Lilly;Novolin® R, Novo Nordisk); intermediate-acting insulins such as NPH(isophane) human insulin (Humulin® N, Lilly; Novolin® N, Novo Nordisk);long-acting insulins such as insulin detemir (Levemir®, Novo Nordisk)and insulin glargine (Lantus®, Sanofi-Aventis); and insulin mixtures,for example, NPH/regular mixtures, such as 70% NPH/30% regular (Humulin®70/30, Lilly; Novolin® 70/30, Novo Nordisk), protamine/lispro mixtures,such as 50% protamine/50% lispro (Humalog® Mix 50/50, Lilly) and 75%protamine/25%; ispro (Humalog® Mix 75/25, Lilly), and protamine/aspartmixtures, such as 70% protamine/30% aspart (Novolog® Mix 70/30, NovoNorkisk); and generic versions thereof. Commercially available insulinpreparations, and generics thereof, are available in vials, cartridges,disposable pens, and/or inhalers.

Some insulin preparations disclosed herein, which may be commercially orotherwise available in pre-loaded vials, cartridges, syringes, inhalersor pens, may alternatively be incorporated or loaded into a device asdisclosed herein, for release and topical delivery of the insulinformulation to the gastrointestinal tract of a subject.

In some embodiments, an insulin preparation as described herein can befurther diluted prior to administration, for example, with 0.9% sodiumchloride, 5% dextrose, or 10% dextrose with 40 mmol/L potassiumchloride.

Dosages

In some embodiments of the devices and methods described herein, theamount of the therapeutic that is administered is about 0.01 mg to about500 mg. In some embodiments, the therapeutic is a therapeutic agent asdisclosed herein. In some embodiments of any of the methods describedherein, the therapeutic is an antibody or an antigen-binding antibodyfragment. In some embodiments of any of the methods described herein,the antibody is a humanized antibody.

In some embodiments, a formulation can include a dose of about 0.01-1.0mg, about 0.1-1.0 mg, about 0.5-5.0 mg, about 1.0-5 mg, about 2.0-10 mg,about 5.0-20 mg, about 5.0-30 mg, about 30-90 mg, about 70-90 mg, about30-110 mg, about 70-110 mg, about 150-450 mg, or about 300-1200 mg of atherapeutic agent. In some embodiments, the therapeutic agent is anantibody, an antigen-binding portion or a biosimilar thereof, or othertherapeutic protein. In some embodiments, an effective dose of thetherapeutic agent in a formulation is about 30 mg, about 40 mg, about 50mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,about 125 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg,about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg,about 750 mg, about 1000 mg, or about 1200 mg. In some embodiments, thedose is an induction dose. In other embodiments, the dose is amaintenance dose.

In some embodiments, the subject is administered the dose of thetherapeutic once a day. In some embodiments, the subject is administeredthe dose of the therapeutic once every two days. In some embodiments,the subject is administered the dose of the therapeutic once every threedays. In some embodiments, the subject is administered the dose of thetherapeutic once every four days. In some embodiments, the subject isadministered the dose of the therapeutic once every five days. In someembodiments, the subject is administered the dose of the therapeuticonce every six days. In some embodiments, the subject is administeredthe dose of the therapeutic once every seven days. In some embodiments,the subject is administered the dose of the therapeutic once every eightdays. In some embodiments, the subject is administered the dose of thetherapeutic once every nine days. In some embodiments, the subject isadministered the dose of the therapeutic once every ten days. In someembodiments, the subject is administered the dose of the therapeuticonce every two weeks. In some embodiments, the subject is administeredthe dose of the therapeutic once every three weeks. In some embodiments,the subject is administered the dose of the therapeutic once everymonth.

In some embodiments, the amount of therapeutic agent absorbed by thebody, as measured in blood or plasma over time and expressed as AUCday/mL), when delivered using any of the devices or methods describedherein, is between about 10% and about 95% of the amount when thetherapeutic agent is administered subcutaneously or intramuscularly(IM), such as about 10% to about 90%, about 10% to about 80%, about 10%to about 70%, about 10% to about 60%, about 10% to about 50%, about 10%to about 40%, about 10% to about 30%, about 10% to about 20%, about 20%to about 95%, about 20% to about 90%, about 20% to about 80%, about 20%to about 70%, about 20% to about 60%, about 20% to about 50%, about 20%to about 40%, about 20% to about 30%, about 30% to about 95%, about 30%to about 90%, about 30% to about 80%, about 30% to about 70%, about 30%to about 60%, about 30% to about 50%, about 30% to about 40%, about 40%to about 95%, about 40% to about 90%, about 40% to about 80%, about 40%to about 70%, about 40% to about 60%, about 40% to about 50%, about 50%to about 95%, about 50% to about 90%, about 50% to about 80%, about 50%to about 70%, about 50% to about 60%, about 60% to about 95%, about 60%to about 90%, about 60% to about 80%, about 60% to about 70%, about 70%to about 95%, about 70% to about 90%, about 70% to about 80%, about 80%to about 95%, about 80% to about 90%, about 90% to about 95%, or about10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, or about 95% of the amount whenthe therapeutic agent is administered subcutaneously or intramuscularly(IM).

In some embodiments, the amount of therapeutic agent absorbed by thebody, as measured in blood or plasma over time and expressed as AUC(μg·day/mL), when delivered using any of the devices or methodsdescribed herein, is between about 10% and about 95% of the amount whenthe therapeutic agent is administered intravenously, such as about 10%to about 90%, about 10% to about 80%, about 10% to about 70%, about 10%to about 60%, about 10% to about 50%, about 10% to about 40%, about 10%to about 30%, about 10% to about 20%, about 20% to about 95%, about 20%to about 90%, about 20% to about 80%, about 20% to about 70%, about 20%to about 60%, about 20% to about 50%, about 20% to about 40%, about 20%to about 30%, about 30% to about 95%, about 30% to about 90%, about 30%to about 80%, about 30% to about 70%, about 30% to about 60%, about 30%to about 50%, about 30% to about 40%, about 40% to about 95%, about 40%to about 90%, about 40% to about 80%, about 40% to about 70%, about 40%to about 60%, about 40% to about 50%, about 50% to about 95%, about 50%to about 90%, about 50% to about 80%, about 50% to about 70%, about 50%to about 60%, about 60% to about 95%, about 60% to about 90%, about 60%to about 80%, about 60% to about 70%, about 70% to about 95%, about 70%to about 90%, about 70% to about 80%, about 80% to about 95%, about 80%to about 90%, about 90% to about 95%, or about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, or about 95% of the amount when the therapeutic agent isadministered intravenously.

Bioavailability (AUC) and other measures can be used to assess thepharmacokinetic (PK) characteristics of administration of therapeuticsadministered according to the devices and methods of the disclosure andcompare with other routes of administration. Example PK parametersinclude plasma half-life (t_(1/2) (min)), maximum plasma concentration(C_(max) (pg/mL)), time to maximum plasma concentration (T_(max) (min)),and clearance rate (CL). For individual drugs, pharmacodynamic (PD)characteristics can be measured and compared with other routes ofadministration. PD characteristics can be specific to the drug beingadministered. For example, where insulin is the drug being administered,PD characteristics can include dextrose infusion rate (mg/kg/min) andtotal amount of glucose (mg/kg) infused (from 20% dextrose infusion)required to maintain the target blood glucose concentration, as well asplasma glucose levels at select time points. Tables 12-14 show thenumber of capsules needed for a given relative bioavailability % forseveral exemplary drugs. The asterisk (*) indicates that dosingfrequency can be increased to reduce number of capsules per dose,particularly for Humira and Interferon alpha-2b.

TABLE 12 Relative bioavailability for 0.5 mL ingestible device capsulesof various drugs Commercially Number of Capsules Needed Dosing Available(for a given Relative Bioavailability %) Potential Frequency SelectedDrug Dosing Drug Dose (IFU) Dose Concentration 100% 90% 80% 70% 60% 50%40% 30% 20% Freq.* Humira 40, 80, q 2wk 80 mg 0.4 mL 1.6 1.8 2.0 2.3 2.73.2 4.0 5.3 8.0 q 2wk (ada- 160 mg ~40 mg limumab) Victoza 1.2 mg qd 1.2mg 1 mL 0.4 0.4 0.5 0.6 0.7 0.8 1.0 1.3 2.0 qd (lirag- ~6 mg lutide)Trulicity 0.75 mg q wk 0.75 mg 1.5 mg 0.5 0.6 0.6 0.7 0.8 1.0 1.3 1.72.5 q wk (dulag- ~0.5 mL lutide) Avonex 30 μg q wk 30 μg 0.5 mL 1.0 1.11.3 1.4 1.7 2.0 2.5 3.3 5.0 q wk (interferon ~30 μg beta-1a) Interferon3-30 million 3 times a 15 million 1 mL 0.6 0.7 0.8 0.9 1.0 1.2 1.5 2.03.0 3 times alfa-2b IU week IU ~50 million a week IU Natpara 50-100 μgqd 75 μg 1 mL 0.2 0.2 0.2 0.2 0.3 0.3 0.4 0.5 0.8 qd (para- ~1 mgthyroid hormone; PTH)

TABLE 13 Relative bioavailability for 0.4 mL ingestible device capsulesof various drugs Commercially Number of Capsules Needed Dosing Available(for a given Relative Bioavailability %) Potential Frequency SelectedDrug Dosing Drug Dose (IFU) Dose Concentration 100% 90% 80% 70% 60% 50%40% 30% 20% Freq.* Humira 40, 80, q 2wk 80 mg 0.4 mL 2.0 2.2 2.5 2.9 3.34.0 5.0 6.7 10.0 q 2wk (ada- 160 mg ~40 mg limumab) Victoza 1.2 mg qd1.2 mg 1 mL 0.5 0.6 0.6 0.7 0.8 1.0 1.3 1.7  2.5 qd (lirag- ~6 mglutide) Trulicity 0.75 mg q wk 0.75 mg 1.5 mg 0.6 0.7 0.8 0.9 1.0 1.31.6 2.1  3.1 q wk (dulag- ~0.5 mL lutide) Avonex 30 μg q wk 30 μg 0.5 mL1.3 1.4 1.6 1.8 2.1 2.5 3.1 4.2  6.3 q wk (interferon ~30 μg beta-1a)Interferon 3-30 million 3 times a 15 million 1 mL 0.8 0.8 0.9 1.1 1.31.5 1.9 2.5  3.8 3 times alfa-2b IU week IU ~50 million a week IUNatpara 50-100 μg qd 75 μg 1 mL 0.2 0.2 0.2 0.3 0.3 0.4 0.5 0.6  0.9 qd(para- ~1 mg thyroid hormone; PTH)

TABLE 14 Relative bioavailability for 0.3 mL ingestible device capsulesof various drugs Commercially Number of Capsules Needed Dosing Available(for a given Relative Bioavailability %) Potential Frequency SelectedDrug Dosing Drug Dose (IFU) Dose Concentration 100% 90% 80% 70% 60% 50%40% 30% 20% Freq.* Humira 40, 80, q 2wk 80 mg 0.4 mL 2.7 3.0 3.3 3.8 4.45.3 6.7 8.9 13.3 q 2wk (ada- 160 mg ~40 mg limumab) Victoza 1.2 mg qd1.2 mg 1 mL 0.7 0.7 0.8 1.0 1.1 1.3 1.7 2.2  3.3 qd (lirag- ~6 mglutide) Trulicity 0.75 mg q wk 0.75 mg 1.5 mg 0.8 0.9 1.0 1.2 1.4 1.72.1 2.8  4.2 q wk (dulag- ~0.5 mL lutide) Avonex 30 μg q wk 30 μg 0.5 mL1.7 1.9 2.1 2.4 2.8 3.3 4.2 5.6  8.3 q wk (interferon ~30 μg beta-1a)Interferon 3-30 million 3 times a 15 million 1 mL 1.0 1.1 1.3 1.4 1.72.0 2.5 3.3  5.0 3 times alfa-2b IU week IU ~50 million a week IUNatpara 50-100 μg qd 75 μg 1 mL 0.3 0.3 0.3 0.4 0.4 0.5 0.6 0.8  1.3 qd(para- ~1 mg thyroid hormone; PTH)

TABLE 15 Additional drugs for consideration for delivery via ingestibledevice Potential Dosing Drug Dose Frequency Remicade ® (infliximab) 400mg* q 0, 2, 6, 8 wk Cimzia ® (certolizumab pegol) 400 mg q 4 wk Enbrel ®(etanercept) 50 mg q 2 wk Lantus ® (insulin) sq qd NovoLog ® (insulin)sq qd Bydureon ® (exenatide) 2 mg q wk Tanzeum ® (albiglutide) 30 mg qwk Growth hormone-inhibiting 0.48-2 mg* qd hormone (GHIH; somatostatin)Sandostatin ® (octreotide) 100-500 μg qd; bid; tid Avastin ®(bevacizumab) 5 mg q 2 wk; 3 wk Entyvio ® (vedolizumab) 300 mg Fragmin ®(dalteparin) 2500-18000 IU qd Rocephin ® (ceftriaxone) (or 1 g qd otherantimicrobials) Genotropin ® (human growth 0.2-2 mg qd hormone; HGH)

Tables 16 and 17 show illustrative dosing regimens for differenttherapeutics agents delivered with ingestible devices described herein.For the purposes of the tables, the ingestible devices have twodifferent payload sizes: 200 μL in 00-sized device and 400 μL in000-sized device. The dosing regimens were generated using a model thataccounts for different therapeutic agent characteristics (e.g., approveddose, approved dosing frequency, and bioavailability via intravenous(IV), subcutaneous (SC) or intramuscular (IM) administration). The modelassumes each drug can be formulated for the device to a maximumconcentration of 175 mg/mL. Given the payload size, therapeutic agentcharacteristics, and a 175 mg/mL drug concentration, bioavailabilitybenchmarks (“Required Bioavailability”) for different dosing regimens(“PGN Regimen”) are shown in the table. For example, as shown in Table16 for adalimumab, an approved 40 mg subcutaneous injection provides aneffective dose of 25.6 mg given adalimumab's subcutaneousbioavailability of 64%. This dose is approved in the U.S. forsubcutaneous administration every two weeks. Administration ofadalimumab at a concentration of 175 mg/mL using a 000-sized ingestibledevice with a payload of 400 μL achieves the same effective dose whenadministered weekly (qwk) given a bioavailability of 18.3%. Likewise,using a 00-sized ingestible device with a payload of 200 μL achieves thesame effective dose when administered daily (qd) given a bioavailabilityof 5.2%. If, for example, the bioavailability for the ingestible deviceis fixed at 25% for a therapeutic agent, similar calculations can beused to calculate the required drug concentration to achieve a desiredeffective dose.

Table 17 provides the same information for a different set oftherapeutic agents. For non-approved therapeutic agents, doseinformation was sourced from publicly available clinical trialinformation. Also, for dose based on patient weight, the assumed weightis 70 kg.

TABLE 16 Approved Dosing Info 000 Capsule Dosing Profile 00 CapsuleDosing Profile Dose Bio Eff Dose PGN Req. PGN Req. Drug Name (mg) Avail(mg) Freq Admin Regimen Bioav. Regimen Bioav. Class adalimumab 40  64%25.6 q2wk SC qwk 18.3% qd 5.2% TNF etanercept 50  58% 29.0 qwk SC qwk41.4% qd 11.8% TNF semaglutide 0.5  89% 0.45 qwk SC qwk 0.6% qwk 1.3%GLP-1 dulaglutide 0.75  65% 0.49 qwk SC qwk 0.7% qwk 1.4% GLP-1interferon beta-1a 0.03  40% 0.01 qwk IM qwk 0.02% qwk 0.03% Interferonbeta alirocumab 75  85% 63.8 q2wk SC qwk 45.5% qd 13.0% PCSK9 evolocumab140  82% 114.8 q2wk SC qwk 82.0% qd 23.4% PCSK9 emicizumab 105  85% 89.3qwk SC qd 18.2% qd 36.4% ACP ustekinumab 45  78% 35.1 q12wk SC q8wk33.4% q4wk 33.4% IL-12/23 pegfilgrastim 6  70% 4.2 x1 SC qd 6.0% qd12.0% GCSF denosumab 60  61% 36.6 q6mo SC q8wk 16.1% q8wk 32.2%Osteoclast golimumab 50  51% 25.5 qmo SC q4wk 36.4% q2wk 36.4% TNFcertolizumab pegol 200  80% 160 q2wk SC qd 16.3% qd 32.7% TNFvedolizumab 300 100% 300 q8wk IV qwk 53.6% qd 15.3% Intergrinsecukinumab 150  73% 109.5 q4wk SC qwk 39.1% qd 11.2% IL-17 abatacept125  79% 98.8 qwk SC qd 20.2% qd 40.3% CD28 inhibitor natalizumab 300100% 300 q4wk IV qd 15.3% qd 30.6% Intergrin tocilizumab 162  80% 129.6qwk SC qd 26.4% qd 52.9% IL-6 teriparatide 0.02  95% 0.02 qd SC qd 0.03%qd 0.05% Parathyroid sargramostim 0.25 100% 0.025 qd IV qd 0.66% qd1.32% GM-CSF

TABLE 17 Baseline dose Dose Eff. Dose PGN Drug Target-based Actions (mg)Bioavail. (mg) Freq. Admin. Regimen Notes Hemophilia A + B concizumabTissue factor pathway inhibitor 17.5  93.0% 16.3 qd SC qd Feasible; min.bioavailability of inhibitor 32.6% (0.35 mg/kg) or 23.3% (0.25 mg/kg)required for 000 capsule Growth disorders somatropin Growth hormoneligand; Skeletal 1.0  80.5% 0.8 qd SC qd Feasible; min. bioavailabilityof muscle MLCK stimulator 2.3% required for 00 capsule somapacitanGrowth hormone ligand; Insulin 11.2 100.0% 11.20 qwk SC qwk Feasible;min. bioavailability of like GF1 ligand modulator 32% required for 00capsule Obesity AM-833 Amylin receptor agonist 2.4 100.0% 2.4 qwk SC qwkFeasible; min. bioavailability of 6.9% required for 00 capsule NN-9277Glucagon receptor agonist; GLP-1 6 100.0% 6.0 qwk SC qwk Feasible; min.bioavailability of agonist 17.1% required for 00 capsule NN-9775 PeptideYY ligand 2.4 100.0% 2.4 x1 SC qd Feasible; min. bioavailability of 6.9%required for 00 capsule Diabetes glucagon 2 100.0% 2.0 qd SC qdFeasible; min. bioavailability of (SC) 5.7% required for 00 capsule

In some embodiments of any of the devices or methods described herein,the effective amount of the therapeutic administered is generally lessthan an amount that is effective when the therapeutic is administeredsubcutaneously, intramuscularly, or intravenously. In some embodimentsof any of the methods described herein, the methods includeadministering (i) an amount of the therapeutic that is a maintenancedose. In some embodiments of any of the methods described herein, themethods include administering (i) an amount of the therapeutic that isan induction dose. Some embodiments of any of the methods describedherein further include (ii) administering an amount of the therapeuticthat is a maintenance dose following the administration of the inductiondose. In some embodiments of any of the methods described herein, theinduction dose is administered by another delivery means, for example,topically, subcutaneously, intramuscularly, or intravenously. In someembodiments of any of the methods described herein, step (ii) isrepeated one or more times. In some embodiments of any of the methodsdescribed herein, step (ii) is repeated once a day, once every two days,once every three days, once every four days, once every five days, oncea week over a period of about 6-8 weeks.

In some embodiments of any of the methods described herein, theinduction dose is equal to the maintenance dose. In some embodiments ofany of the methods described herein, the induction dose is greater thanthe maintenance dose. In some embodiments of any of the methodsdescribed herein, the induction dose is 5 times greater than themaintenance dose. In some embodiments of any of the methods describedherein, the induction dose is 2 times greater than the maintenance dose.

In some embodiments, the release mechanism is an actuation system. Insome embodiments, the release mechanism is an enteric actuation system.In some embodiments, the release mechanism is a mechanical actuationsystem. In some embodiments, the release mechanism is an electricalactuation system. In some embodiments, the actuation system comprises anenteric actuation system coupled to a mechanical actuation system. Insome embodiments, the actuation system comprises a pre-pressurized airreservoir that drives a piston.

In some embodiments, the formulation comprises a therapeuticallyeffective amount of the therapeutic agent as disclosed herein. In someembodiments, the formulation comprises a human equivalent dose (HED) ofthe therapeutic agent as disclosed herein.

Methods of Treatment

In some embodiments, provided herein is a method of treating a diseaseas disclosed herein, the method comprising: administering to the subjecta pharmaceutical formulation that comprises a therapeutic agent asdisclosed herein, wherein the pharmaceutical formulation is released ata location in the gastrointestinal tract of the subject. In someembodiments, the pharmaceutical formulation is released from the devicewith sufficient power, pressure and/or force for trans-epithelialdelivery of the therapeutic agent to the gastrointestinal tract. In someembodiments, the pharmaceutical formulation is released from the devicewith sufficient power, pressure and/or force for epithelial delivery ofthe therapeutic agent to the gastrointestinal tract. In someembodiments, the pharmaceutical formulation is released from the devicewith sufficient power, pressure and/or force for topical delivery of thetherapeutic agent to the gastrointestinal tract.

Trans-Epithelial Administration

In some embodiments, the method comprises trans-epithelialadministration of a therapeutic agent to the GI tract of the subject. Insome embodiments, the method provides systemic uptake of the therapeuticagent of about 10% to about 99%, for example, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 55%, at least about 60%, at least about65%, at least about 70%, at least about 75%, at least about 80%, atleast about 85%, or at least about 90%, relative to intravenous orsubcutaneous administration of the same amount of the therapeutic agent.In some embodiments, the same amount of therapeutic agent is an approvedor commercially-available dose. In some more particular embodiments, thesystemic uptake is at least about 10% relative to intravenous orsubcutaneous administration of the same amount of the therapeutic agent.In other embodiments, the systemic uptake is at least about 15% relativeto intravenous or subcutaneous administration of the same amount of thetherapeutic agent. In yet other embodiments, the systemic uptake is atleast about 20% relative to intravenous or subcutaneous administrationof the same amount of the therapeutic agent. In yet other embodiments,the systemic uptake is at least about 25% relative to intravenous orsubcutaneous administration of the same amount of the therapeutic agent.In yet other embodiments, the systemic uptake is at least about 30%relative to intravenous or subcutaneous administration of the sameamount of the therapeutic agent. In yet other embodiments, the systemicuptake is at least about 35% relative to intravenous or subcutaneousadministration of the same amount of the therapeutic agent. In yet otherembodiments, the systemic uptake is at least about 40%, or even higher,relative to intravenous or subcutaneous administration of the sameamount of the therapeutic agent.

In some embodiments, the trans-epithelial administration provides anarea under a curve (AUC_(TE)) of the therapeutic agent in systemiccirculation versus time of about 10% to about 99%, for example, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 55%, at least about 60%,at least about 65%, at least about 70%, at least about 75%, at leastabout 80%, at least about 85%, or at least about 90% as the AUC obtainedwhen the same amount of the therapeutic agent is delivered intravenously(to the same subject, or to a population of subjects) (AUC_(IV)). Insome embodiments, the same amount of therapeutic agent is an approved orcommercially-available dose. In some more particular embodiments, thearea under a curve (AUC_(TE)) of the therapeutic agent in systemiccirculation versus time is at least about 15% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously(AUC_(IV)). In some other embodiments, the area under a curve (AUC_(TE))of the therapeutic agent in systemic circulation versus time is at leastabout 20% of the AUC obtained when the same amount of the therapeuticagent is delivered intravenously (AUC_(IV)). In some other embodiments,the area under a curve (AUC_(TE)) of the therapeutic agent in systemiccirculation versus time is at least about 25% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously(AUC_(IV)). In some other embodiments, the area under a curve (AUC_(TE))of the therapeutic agent in systemic circulation versus time is at leastabout 30% of the AUC obtained when the same amount of the therapeuticagent is delivered intravenously (AUC_(IV)). In some other embodiments,the area under a curve (AUC_(TE)) of the therapeutic agent in systemiccirculation versus time is at least about 35% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously(AUC_(IV)). In some other embodiments, the area under a curve (AUC_(TE))of the therapeutic agent in systemic circulation versus time is at leastabout 40% of the AUC obtained when the same amount of the therapeuticagent is delivered intravenously (AUC_(IV)). In some other embodiments,the area under a curve (AUC_(TE)) of the therapeutic agent in systemiccirculation versus time is at least about 45% of the AUC obtained whenthe same amount of the therapeutic agent is administered intravenously(AUC_(IV)). In some embodiments, particularly when an AUC is determinedfrom a plurality of subjects, the AUC is a mean AUC obtained from theplurality of subjects. Thus, in some further embodiments, AUC_(TE) orAUC_(IV) may refer to a mean AUC_(TE) or mean AUC_(IV), respectively. Insome other embodiments, an individual AUC value obtained for a singlesubject may be compared to a mean AUC obtained from a plurality ofsubjects.

In some embodiments, the trans-epithelial administration provides anarea under a curve (AUC_(TE)) of the therapeutic agent in systemiccirculation versus time of about 10% to about 99%, for example, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 55%, at least about 60%,at least about 65%, at least about 70%, at least about 75%, at leastabout 80%, at least about 85%, or at least about 90% as the AUC obtainedwhen the same amount of the therapeutic agent is deliveredsubcutaneously (to the same subject, or to a population of subjects)(AUC_(SC)). In some embodiments, the same amount of therapeutic agent isan approved or commercially-available dose. In some more particularembodiments, the area under a curve (AUC_(TE)) of the therapeutic agentin systemic circulation versus time is at least about 15% of the AUCobtained when the same amount of the therapeutic agent is deliveredsubcutaneously (AUC_(SC)). In some other embodiments, the area under acurve (AUC_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 20% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously (AUC_(SC)). In someother embodiments, the area under a curve (AUC_(TE)) of the therapeuticagent in systemic circulation versus time is at least about 25% of theAUC obtained when the same amount of the therapeutic agent is deliveredsubcutaneously (AUC_(SC)). In some other embodiments, the area under acurve (AUC_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 30% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously (AUC_(SC)). In someother embodiments, the area under a curve (AUC_(TE)) of the therapeuticagent in systemic circulation versus time is at least about 35% of theAUC obtained when the same amount of the therapeutic agent is deliveredsubcutaneously (AUC_(SC)). In some other embodiments, the area under acurve (AUC_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 40% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously (AUC_(SC)). In someother embodiments, the area under a curve (AUC_(TE)) of the therapeuticagent in systemic circulation versus time is at least about 45% of theAUC obtained when the same amount of the therapeutic agent isadministered subcutaneously (AUC_(SC)). In some embodiments,particularly when an AUC is determined from a plurality of subjects, theAUC is a mean AUC obtained from the plurality of subjects. Thus, in somefurther embodiments, AUC_(TE) or AUC_(SC) may refer to a mean AUC_(TE)or mean AUC_(SC), respectively. In some other embodiments, an individualAUC value obtained for a single subject may be compared to a mean AUCobtained from a plurality of subjects.

In some embodiments, the trans-epithelial administration provides anarea under a curve (AUC_(TE)) of the therapeutic agent in systemiccirculation versus time that is at least about 100%, at least about150%, at least about 200%, at least about 250%, at least about 300%, atleast about 400%, at least about 500%, at least about 600%, at leastabout 700%, at least about 800%, at least about 900%, at least about1000%, at least about 1100%, at least about 1200%, at least about 1300%,at least about 1400%, at least about 1500%, at least about 1600%, atleast about 1700%, at least about 1800%, at least about 1900%, at leastabout 2000%, at least about 2200%, at least about 2300%, at least about2400%, at least about 2500%, at least about 2600%, at least about 2700%,at least about 2800%, at least about 2900%, at least about 3000%, atleast about 3100%, at least about 3200%, at least about 3300%, at leastabout 3400%, at least about 3500%, at least about 3600%, at least about3700%, at least about 3800%, at least about 3900%, at least about 4000%,at least about 4100%, at least about 4200%, at least about 4300%, atleast about 4400%, at least about 4500%, at least about 4600%, at leastabout 4700%, at least about 4800%, at least about 4900%, at least about5000%, at least about 5100%, at least about 5200%, at least about 5300%,at least about 5400%, at least about 5500%, at least about 5600%, atleast about 5700%, at least about 5800%, at least about 5900%, at leastabout 6000%, at least about 6100%, at least about 6200%, at least about6300%, at least about 6400%, at least about 6500%, at least about 6600%,at least about 6700%, at least about 6800%, at least about 6900%, atleast about 7000%, at least about 7100%, at least about 7200%, at leastabout 7300%, at least about 7400%, at least about 7500%, at least about7600%, at least about 7700%, at least about 7800%, at least about 7900%,at least about 8000%, at least about 8100%, at least about 8200%, atleast about 8300%, at least about 8400%, at least about 8500%, at leastabout 8600%, at least about 8700%, at least about 8800%, at least about8900%, at least about 9000%, at least about 9100%, at least about 9200%,at least about 9300%, at least about 9400%, at least about 9500%, atleast about 9600%, at least about 9700%, at least about 9800%, at leastabout 9900%, or at least about 10,000% as that obtained when the sameamount of the therapeutic agent is administered orally (to the samesubject, or to a population of subjects). In some embodiments, the sameamount of therapeutic agent is an approved or commercially-availabledose. In some embodiments, the AUC is the mean AUC.

In some embodiments, the trans-epithelial administration provides amaximum plasma concentration ((C_(max))_(TE)) of the therapeutic agentin systemic circulation versus time of about 10% to about 99%, forexample, at least about 10%, at least about 15%, at least about 20%, atleast about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, at least about 55%, atleast about 60%, at least about 65%, at least about 70%, at least about75%, at least about 80%, at least about 85%, or at least about 90% asthe AUC obtained when the same amount of the therapeutic agent isdelivered intravenously (to the same subject, or to a population ofsubjects) ((C_(max))_(IV)). In some embodiments, the same amount oftherapeutic agent is an approved or commercially-available dose. In somemore particular embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 15% of the AUC obtained when the same amount ofthe therapeutic agent is delivered intravenously ((C_(max))_(IV)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 20% of the AUC obtained when the same amount ofthe therapeutic agent is delivered intravenously ((C_(max))_(IV)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 25% of the AUC obtained when the same amount ofthe therapeutic agent is delivered intravenously ((C_(max))_(IV)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 30% of the AUC obtained when the same amount ofthe therapeutic agent is delivered intravenously ((C_(max))_(IV)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 35% of the AUC obtained when the same amount ofthe therapeutic agent is delivered intravenously ((C_(max))_(IV)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 40% of the AUC obtained when the same amount ofthe therapeutic agent is delivered intravenously ((C_(max))_(IV)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 45% of the AUC obtained when the same amount ofthe therapeutic agent is delivered intravenously ((C_(max))_(IV)). Insome embodiments, particularly when the C_(max) is determined from aplurality of subjects, the C_(max) is a mean C_(max) obtained from theplurality of subjects. Thus, in some further embodiments, (C_(max))_(TE)or (C_(max))_(IV) may refer to a mean (C_(max))_(TE) or mean(C_(max))_(IV), respectively. In some other embodiments, an individualC_(max) value obtained for a single subject may be compared to a meanC_(max) obtained from a plurality of subjects.

In some embodiments, the trans-epithelial administration provides amaximum plasma concentration ((C_(max))_(TE)) of the therapeutic agentin systemic circulation versus time of about 10% to about 99%, forexample, at least about 10%, at least about 15%, at least about 20%, atleast about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, at least about 55%, atleast about 60%, at least about 65%, at least about 70%, at least about75%, at least about 80%, at least about 85%, or at least about 90% asthe AUC obtained when the same amount of the therapeutic agent isdelivered subcutaneously (to the same subject, or to a population ofsubjects) ((C_(max))_(SC)). In some embodiments, the same amount oftherapeutic agent is an approved or commercially-available dose. In somemore particular embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 15% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously ((C_(max))_(SC)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 20% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously ((C_(max))_(SC)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 25% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously ((C_(max))_(SC)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 30% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously ((C_(max))_(SC)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 35% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously ((C_(max))_(SC)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 40% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously ((C_(max))_(SC)). Insome other embodiments, the maximum plasma concentration((C_(max))_(TE)) of the therapeutic agent in systemic circulation versustime is at least about 45% of the AUC obtained when the same amount ofthe therapeutic agent is delivered subcutaneously ((C_(max))_(SC)). Insome embodiments, particularly when the C_(max) is determined from aplurality of subjects, the C_(max) is a mean C_(max) obtained from theplurality of subjects. Thus, in some further embodiments, (C_(max))_(TE)or (C_(max))_(SC) may refer to a mean (C_(max))_(TE) or mean(C_(max))_(SC), respectively. In some other embodiments, an individualC_(max) value obtained for a single subject may be compared to a meanC_(max) obtained from a plurality of subjects.

Epithelial Administration

In some embodiments, the method comprises epithelial administration of atherapeutic agent to the GI tract of the subject. In some embodiments,the method provides systemic uptake of the therapeutic agent of about10% to about 99%, for example, at least about 10%, at least about 15%,at least about 20%, at least about 25%, at least about 30%, at leastabout 35%, at least about 40%, at least about 45%, at least about 50%,at least about 55%, at least about 60%, at least about 65%, at leastabout 70%, at least about 75%, at least about 80%, at least about 85%,or at least about 90%, relative to topical delivery or a non-device oraldelivery. In some embodiments, the same amount of therapeutic agent isan approved or commercially-available dose. In some more particularembodiments, the systemic uptake is at least about 10% relative totopical delivery or non-device oral delivery of the same amount of thetherapeutic agent. In other embodiments, the systemic uptake is at leastabout 15% relative to topical delivery or non-device oral delivery ofthe same amount of the therapeutic agent. In yet other embodiments, thesystemic uptake is at least about 20% relative to topical delivery ornon-device oral delivery of the same amount of the therapeutic agent. Inyet other embodiments, the systemic uptake is at least about 25%relative to topical delivery or non-device oral delivery of the sameamount of the therapeutic agent. In yet other embodiments, the systemicuptake is at least about 30% relative to topical delivery or non-deviceoral delivery of the same amount of the therapeutic agent. In yet otherembodiments, the systemic uptake is at least about 35% relative totopical delivery or non-device oral delivery of the same amount of thetherapeutic agent. In yet other embodiments, the systemic uptake is atleast about 40%, or even higher, relative to topical delivery ornon-device oral delivery of the same amount of the therapeutic agent.

In some embodiments, the epithelial administration provides systemicuptake of the therapeutic agent of about 0.5% to about 10% or more, forexample, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%,about 6%, about 7%, about 8%, about 9%, about 10%, or more, relative tointravenous or subcutaneous administration of the same amount of thetherapeutic agent. In some embodiments, the same amount of therapeuticagent is an approved or commercially-available dose. In some moreparticular embodiments, the systemic uptake is at least about 0.5%relative to intravenous or subcutaneous administration of the sameamount of the therapeutic agent. In other embodiments, the systemicuptake is at least about 2% relative to intravenous or subcutaneousadministration of the same amount of the therapeutic agent. In yet otherembodiments, the systemic uptake is at least about 3% relative tointravenous or subcutaneous administration of the same amount of thetherapeutic agent. In yet other embodiments, the systemic uptake is atleast about 4% relative to intravenous or subcutaneous administration ofthe same amount of the therapeutic agent. In yet other embodiments, thesystemic uptake is at least about 5% relative to intravenous orsubcutaneous administration of the same amount of the therapeutic agent.In yet other embodiments, the systemic uptake is at least about 6%relative to intravenous or subcutaneous administration of the sameamount of the therapeutic agent. In yet other embodiments, the systemicuptake is at least about 7% relative to intravenous or subcutaneousadministration of the same amount of the therapeutic agent. In yet otherembodiments, the systemic uptake is at least about 8% relative tointravenous or subcutaneous administration of the same amount of thetherapeutic agent. In yet other embodiments, the systemic uptake is atleast about 9% relative to intravenous or subcutaneous administration ofthe same amount of the therapeutic agent. In yet other embodiments, thesystemic uptake is at least about 10%, or even higher, relative tointravenous or subcutaneous administration of the same amount of thetherapeutic agent.

In some embodiments, the systemic uptake of the therapeutic agent isgreater than the systemic uptake provided by topical administration ofthe same amount of the therapeutic agent, but less than the systemicuptake provided by trans-epithelial administration of the same amount ofthe therapeutic agent. In some embodiments, epithelial administrationprovides systemic uptake of the therapeutic agent of about 10%, about15%, about 20%, about about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 100%, about 125%, about 150%,about 175%, about 200%, about 225%, about 250%, about 275%, about 300%,about 325%, about 350%, about 375%, about 400%, about 425%, about 450%,about 475%, or about 500% greater than the systemic uptake of the sameamount of the therapeutic agent provided by topical administration. Insome embodiments, the same amount of therapeutic agent is an approved orcommercially-available dose.

In some embodiments, the epithelial administration provides an areaunder a curve (AUC_(E)) of the therapeutic agent in systemic circulationversus time of about 10% to about 99%, for example, at least about 10%,at least about 15%, at least about 20%, at least about 25%, at leastabout 30%, at least about 35%, at least about 40%, at least about 45%,at least about 50%, at least about 55%, at least about 60%, at leastabout 65%, at least about 70%, at least about 75%, at least about 80%,at least about 85%, or at least about 90% as the AUC obtained when thesame amount of the therapeutic agent is delivered intravenously (to thesame subject, or to a population of subjects) (AUC_(IV)). In someembodiments, the same amount of therapeutic agent is an approved orcommercially-available dose. In some more particular embodiments, thearea under a curve (AUC_(E)) of the therapeutic agent in systemiccirculation versus time is at least about 15% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously(AUC_(IV)). In some other embodiments, the area under a curve (AUC_(E))of the therapeutic agent in systemic circulation versus time is at leastabout 20% of the AUC obtained when the same amount of the therapeuticagent is delivered intravenously (AUC_(IV)). In some other embodiments,the area under a curve (AUC_(E)) of the therapeutic agent in systemiccirculation versus time is at least about 25% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously(AUC_(IV)). In some other embodiments, the area under a curve (AUC_(E))of the therapeutic agent in systemic circulation versus time is at leastabout 30% of the AUC obtained when the same amount of the therapeuticagent is delivered intravenously (AUC_(IV)). In some other embodiments,the area under a curve (AUC_(T)) of the therapeutic agent in systemiccirculation versus time is at least about 35% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously(AUC_(IV)). In some other embodiments, the area under a curve (AUC_(E))of the therapeutic agent in systemic circulation versus time is at leastabout 40% of the AUC obtained when the same amount of the therapeuticagent is delivered intravenously (AUC_(IV)). In some other embodiments,the area under a curve (AUC_(E)) of the therapeutic agent in systemiccirculation versus time is at least about 45% of the AUC obtained whenthe same amount of the therapeutic agent is administered intravenously(AUC_(IV)). In some embodiments, particularly when an AUC is determinedfrom a plurality of subjects, the AUC is a mean AUC obtained from theplurality of subjects. Thus, in some further embodiments, AUC_(E) orAUC_(IV) may refer to a mean AUC_(E) or mean AUC_(IV), respectively. Insome other embodiments, an individual AUC value obtained for a singlesubject may be compared to a mean AUC obtained from a plurality ofsubjects.

In some embodiments, the epithelial administration provides an areaunder a curve (AUC_(E)) of the therapeutic agent in systemic circulationversus time of about 10% to about 99%, for example, at least about 10%,at least about 15%, at least about 20%, at least about 25%, at leastabout 30%, at least about 35%, at least about 40%, at least about 45%,at least about 50%, at least about 55%, at least about 60%, at leastabout 65%, at least about 70%, at least about 75%, at least about 80%,at least about 85%, or at least about 90% as the AUC obtained when thesame amount of the therapeutic agent is delivered subcutaneously (to thesame subject, or to a population of subjects) (AUC_(SC)). In someembodiments, the same amount of therapeutic agent is an approved orcommercially-available dose. In some more particular embodiments, thearea under a curve (AUC_(E)) of the therapeutic agent in systemiccirculation versus time is at least about 15% of the AUC obtained whenthe same amount of the therapeutic agent is delivered subcutaneously(AUC_(SC)). In some other embodiments, the area under a curve (AUC_(E))of the therapeutic agent in systemic circulation versus time is at leastabout 20% of the AUC obtained when the same amount of the therapeuticagent is delivered subcutaneously (AUC_(SC)). In some other embodiments,the area under a curve (AUC_(E)) of the therapeutic agent in systemiccirculation versus time is at least about 25% of the AUC obtained whenthe same amount of the therapeutic agent is delivered subcutaneously(AUC_(SC)). In some other embodiments, the area under a curve (AUC_(E))of the therapeutic agent in systemic circulation versus time is at leastabout 30% of the AUC obtained when the same amount of the therapeuticagent is delivered subcutaneously (AUC_(SC)). In some other embodiments,the area under a curve (AUC_(E)) of the therapeutic agent in systemiccirculation versus time is at least about 35% of the AUC obtained whenthe same amount of the therapeutic agent is delivered subcutaneously(AUC_(SC)). In some other embodiments, the area under a curve (AUC_(E))of the therapeutic agent in systemic circulation versus time is at leastabout 40% of the AUC obtained when the same amount of the therapeuticagent is delivered subcutaneously (AUC_(SC)). In some other embodiments,the area under a curve (AUC_(E)) of the therapeutic agent in systemiccirculation versus time is at least about 45% of the AUC obtained whenthe same amount of the therapeutic agent is administered subcutaneously(AUC_(SC)). In some embodiments, particularly when an AUC is determinedfrom a plurality of subjects, the AUC is a mean AUC obtained from theplurality of subjects. Thus, in some further embodiments, AUC_(E) orAUC_(SC) may refer to a mean AUC_(E) or mean AUC_(SC), respectively. Insome other embodiments, an individual AUC value obtained for a singlesubject may be compared to a mean AUC obtained from a plurality ofsubjects.

In some embodiments, the epithelial administration provides an areaunder a curve (AUC_(E)) of the therapeutic agent in systemic circulationversus time that is at least about 100%, at least about 150%, at leastabout 200%, at least about 250%, at least about 300%, at least about400%, at least about 500%, at least about 600%, at least about 700%, atleast about 800%, at least about 900%, at least about 1000%, at leastabout 1100%, at least about 1200%, at least about 1300%, at least about1400%, at least about 1500%, at least about 1600%, at least about 1700%,at least about 1800%, at least about 1900%, at least about 2000%, atleast about 2200%, at least about 2300%, at least about 2400%, at leastabout 2500%, at least about 2600%, at least about 2700%, at least about2800%, at least about 2900%, at least about 3000%, at least about 3100%,at least about 3200%, at least about 3300%, at least about 3400%, atleast about 3500%, at least about 3600%, at least about 3700%, at leastabout 3800%, at least about 3900%, at least about 4000%, at least about4100%, at least about 4200%, at least about 4300%, at least about 4400%,at least about 4500%, at least about 4600%, at least about 4700%, atleast about 4800%, at least about 4900%, at least about 5000%, at leastabout 5100%, at least about 5200%, at least about 5300%, at least about5400%, at least about 5500%, at least about 5600%, at least about 5700%,at least about 5800%, at least about 5900%, at least about 6000%, atleast about 6100%, at least about 6200%, at least about 6300%, at leastabout 6400%, at least about 6500%, at least about 6600%, at least about6700%, at least about 6800%, at least about 6900%, at least about 7000%,at least about 7100%, at least about 7200%, at least about 7300%, atleast about 7400%, at least about 7500%, at least about 7600%, at leastabout 7700%, at least about 7800%, at least about 7900%, at least about8000%, at least about 8100%, at least about 8200%, at least about 8300%,at least about 8400%, at least about 8500%, at least about 8600%, atleast about 8700%, at least about 8800%, at least about 8900%, at leastabout 9000%, at least about 9100%, at least about 9200%, at least about9300%, at least about 9400%, at least about 9500%, at least about 9600%,at least about 9700%, at least about 9800%, at least about 9900%, or atleast about 10,000% as that obtained when the same amount of thetherapeutic agent is administered orally (to the same subject, or to apopulation of subjects). In some embodiments, the same amount oftherapeutic agent is an approved or commercially-available dose. In someembodiments, the AUC is the mean AUC.

In some embodiments, the epithelial administration provides a maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time of about 10% to about 99%, for example,at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, at least about 55%, at leastabout 60%, at least about 65%, at least about 70%, at least about 75%,at least about 80%, at least about 85%, or at least about 90% as the AUCobtained when the same amount of the therapeutic agent is deliveredintravenously (to the same subject, or to a population of subjects)((C_(max))_(IV)). In some embodiments, the same amount of therapeuticagent is an approved or commercially-available dose. In some moreparticular embodiments, the maximum plasma concentration ((C_(max))_(E))of the therapeutic agent in systemic circulation versus time is at leastabout 15% of the AUC obtained when the same amount of the therapeuticagent is delivered intravenously ((C_(max))_(IV)). In some otherembodiments, the maximum plasma concentration ((C_(max))_(E)) of thetherapeutic agent in systemic circulation versus time is at least about20% of the AUC obtained when the same amount of the therapeutic agent isdelivered intravenously ((C_(max))_(IV)). In some other embodiments, themaximum plasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time is at least about 25% of the AUCobtained when the same amount of the therapeutic agent is deliveredintravenously ((C_(max))_(IV)). In some other embodiments, the maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time is at least about 30% of the AUCobtained when the same amount of the therapeutic agent is deliveredintravenously ((C_(max))_(IV)). In some other embodiments, the maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time is at least about 35% of the AUCobtained when the same amount of the therapeutic agent is deliveredintravenously ((C_(max))_(IV)). In some other embodiments, the maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time is at least about 40% of the AUCobtained when the same amount of the therapeutic agent is deliveredintravenously ((C_(max))_(IV)). In some other embodiments, the maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time is at least about 45% of the AUCobtained when the same amount of the therapeutic agent is deliveredintravenously ((C_(max))_(IV)). In some embodiments, particularly whenthe C_(max) is determined from a plurality of subjects, the C_(max) is amean C_(max) obtained from the plurality of subjects. Thus, in somefurther embodiments, (C_(max))_(E) or (C_(max))_(IV) may refer to a mean(C_(max))_(E) or mean (C_(max))_(IV), respectively. In some otherembodiments, an individual C_(max) value obtained for a single subjectmay be compared to a mean C_(max) obtained from a plurality of subjects.

In some embodiments, the epithelial administration provides a maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time of about 10% to about 99%, for example,at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, at least about 55%, at leastabout 60%, at least about 65%, at least about 70%, at least about 75%,at least about 80%, at least about 85%, or at least about 90% as the AUCobtained when the same amount of the therapeutic agent is deliveredsubcutaneously (to the same subject, or to a population of subjects)((C_(max))_(SC)). In some embodiments, the same amount of therapeuticagent is an approved or commercially-available dose. In some moreparticular embodiments, the maximum plasma concentration ((C_(max))_(E))of the therapeutic agent in systemic circulation versus time is at leastabout 15% of the AUC obtained when the same amount of the therapeuticagent is delivered subcutaneously ((C_(max))_(SC)). In some otherembodiments, the maximum plasma concentration ((C_(max))_(E)) of thetherapeutic agent in systemic circulation versus time is at least about20% of the AUC obtained when the same amount of the therapeutic agent isdelivered subcutaneously ((C_(max))_(SC)). In some other embodiments,the maximum plasma concentration ((C_(max))_(E)) of the therapeuticagent in systemic circulation versus time is at least about 25% of theAUC obtained when the same amount of the therapeutic agent is deliveredsubcutaneously ((C_(max))_(SC)). In some other embodiments, the maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time is at least about 30% of the AUCobtained when the same amount of the therapeutic agent is deliveredsubcutaneously ((C_(max))_(SC)). In some other embodiments, the maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time is at least about 35% of the AUCobtained when the same amount of the therapeutic agent is deliveredsubcutaneously ((C_(max))_(SC)). In some other embodiments, the maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time is at least about 40% of the AUCobtained when the same amount of the therapeutic agent is deliveredsubcutaneously ((C_(max))_(SC)). In some other embodiments, the maximumplasma concentration ((C_(max))_(E)) of the therapeutic agent insystemic circulation versus time is at least about 45% of the AUCobtained when the same amount of the therapeutic agent is deliveredsubcutaneously ((C_(max))_(SC)). In some embodiments, particularly whenthe C_(max) is determined from a plurality of subjects, the C_(max) is amean C_(max) obtained from the plurality of subjects. Thus, in somefurther embodiments, (C_(max))_(E) or (C_(max))_(SC) may refer to a mean(C_(max))_(E) or mean (C_(max))_(SC), respectively. In some otherembodiments, an individual C_(max) value obtained for a single subjectmay be compared to a mean C_(max) obtained from a plurality of subjects.

Topical Administration

In some embodiments, the method comprises topical administration of atherapeutic agent to the GI tract of the subject. In some embodiments,the method provides systemic uptake of the therapeutic agent of about0.1% to about 20%, for example, at most about 1%, at most about 3%, atmost about 5%, at most about 10%, at most about 15%, or at most about20%, relative to intravenous or subcutaneous administration of the sameamount of the therapeutic agent. In some embodiments, the same amount oftherapeutic agent is an approved or commercially-available dose. In somemore particular embodiments, the systemic uptake is at most about 1%relative to intravenous or subcutaneous administration of the sameamount of the therapeutic agent. In some more particular embodiments,the systemic uptake is at most about 3% relative to intravenous orsubcutaneous administration of the same amount of the therapeutic agent.In other embodiments, the systemic uptake is at most about 5% relativeto intravenous or subcutaneous administration of the same amount of thetherapeutic agent. In yet other embodiments, the systemic uptake is atmost about 10% relative to intravenous or subcutaneous administration ofthe same amount of the therapeutic agent. In yet other embodiments, thesystemic uptake is at most about 15% relative to intravenous orsubcutaneous administration of the same amount of the therapeutic agent.In yet other embodiments, the systemic uptake is at most about 20%relative to intravenous or subcutaneous administration of the sameamount of the therapeutic agent.

In some embodiments, the topical administration provides an area under acurve (AUC_(TOP)) of the therapeutic agent in systemic circulationversus time of about 0.1% to about 20%, for example, at most about 1%,at most about 3%, at most about 5%, at most about 10%, at most about15%, or at most about 20%, as the AUC obtained when the same amount ofthe therapeutic agent is delivered intravenously (to the same subject,or to a population of subjects) (AUC_(IV)). In some embodiments, thesame amount of therapeutic agent is an approved orcommercially-available dose. In some more particular embodiments, thearea under a curve (AUC_(TOP)) of the therapeutic agent in systemiccirculation versus time is at most about 1% of the AUC obtained when thesame amount of the therapeutic agent is delivered intravenously(AUC_(IV)). In some other embodiments, the area under a curve(AUC_(TOP)) of the therapeutic agent in systemic circulation versus timeis at most about 3% of the AUC obtained when the same amount of thetherapeutic agent is delivered intravenously (AUC_(IV)). In some otherembodiments, the area under a curve (AUC_(TOP)) of the therapeutic agentin systemic circulation versus time is at most about 5% of the AUCobtained when the same amount of the therapeutic agent is deliveredintravenously (AUC_(IV)). In some other embodiments, the area under acurve (AUC_(TOP)) of the therapeutic agent in systemic circulationversus time is at most about 10% of the AUC obtained when the sameamount of the therapeutic agent is delivered intravenously (AUC_(IV)).In some other embodiments, the area under a curve (AUC_(TOP)) of thetherapeutic agent in systemic circulation versus time is at most about15% of the AUC obtained when the same amount of the therapeutic agent isdelivered intravenously (AUC_(IV)). In some other embodiments, the areaunder a curve (AUC_(TOP)) of the therapeutic agent in systemiccirculation versus time is at most about 20% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously(AUC_(IV)). In some embodiments, particularly when an AUC is determinedfrom a plurality of subjects, the AUC is a mean AUC obtained from theplurality of subjects. Thus, in some further embodiments, AUC_(TOP) orAUC_(IV) may refer to a mean AUC_(TOP) or mean AUC_(IV), respectively.In some other embodiments, an individual AUC value obtained for a singlesubject may be compared to a mean AUC obtained from a plurality ofsubjects.

In some embodiments, the topical administration provides an area under acurve (AUC_(TOP)) of the therapeutic agent in systemic circulationversus time of about 0.1% to about 20%, for example, at most about 1%,at most about 3%, at most about 5%, at most about 10%, at most about15%, or at most about 20%, as that obtained when the same amount of thetherapeutic agent is delivered subcutaneously (to the same subject, orto a population of subjects) (AUC_(SC)). In some embodiments, the sameamount of therapeutic agent is an approved or commercially-availabledose. In some more particular embodiments, the area under a curve(AUC_(TOP)) of the therapeutic agent in systemic circulation versus timeis at most about 1% of the AUC obtained when the same amount of thetherapeutic agent is delivered subcutaneously (AUC_(SC)). In some otherembodiments, the area under a curve (AUC_(TOP)) of the therapeutic agentin systemic circulation versus time is at most about 3% of the AUCobtained when the same amount of the therapeutic agent is deliveredsubcutaneously (AUC_(SC)). In some other embodiments, the area under acurve (AUC_(TOP)) of the therapeutic agent in systemic circulationversus time is at most about 5% of the AUC obtained when the same amountof the therapeutic agent is delivered subcutaneously (AUC_(SC)). In someother embodiments, the area under a curve (AUC_(TOP)) of the therapeuticagent in systemic circulation versus time is at most about 10% of theAUC obtained when the same amount of the therapeutic agent is deliveredsubcutaneously (AUC_(SC)). In some other embodiments, the area under acurve (AUC_(TOP)) of the therapeutic agent in systemic circulationversus time is at most about 15% of the AUC obtained when the sameamount of the therapeutic agent is delivered subcutaneously (AUC_(SC)).In some other embodiments, the area under a curve (AUC_(TOP)) of thetherapeutic agent in systemic circulation versus time is at most about20% of the AUC obtained when the same amount of the therapeutic agent isdelivered subcutaneously (AUC_(SC)). In some embodiments, particularlywhen an AUC is determined from a plurality of subjects, the AUC is amean AUC obtained from the plurality of subjects. Thus, in some furtherembodiments, AUC_(TOP) or AUC_(SC) may refer to a mean AUC_(TOP) or meanAUC_(SC), respectively. In some other embodiments, an individual AUCvalue obtained for a single subject may be compared to a mean AUCobtained from a plurality of subjects.

In some embodiments, the topical administration provides a maximumplasma concentration ((C_(max))_(TOP)) of the therapeutic agent insystemic circulation versus time of about 0.1% to about 20%, forexample, at most about 1%, at most about 3%, at most about 5%, at mostabout 10%, at most about 15%, or at most about 20%, as that obtainedwhen the same amount of the therapeutic agent is delivered intravenously(to the same subject, or to a population of subjects) ((C_(max))_(IV)).In some embodiments, the same amount of therapeutic agent is an approvedor commercially-available dose. In some more particular embodiments, themaximum plasma concentration ((C_(max))_(TOP)) of the therapeutic agentin systemic circulation versus time is at most about 1% of the AUCobtained when the same amount of the therapeutic agent is deliveredintravenously ((C_(max))_(IV)). In some other embodiments, the maximumplasma concentration ((C_(max))_(TOP)) of the therapeutic agent insystemic circulation versus time is at most about 3% of the AUC obtainedwhen the same amount of the therapeutic agent is delivered intravenously((C_(max))_(IV)). In some other embodiments, the maximum plasmaconcentration ((C_(max))_(TOP)) of the therapeutic agent in systemiccirculation versus time is at most about 5% of the AUC obtained when thesame amount of the therapeutic agent is delivered intravenously((C_(max))_(IV)). In some other embodiments, the maximum plasmaconcentration ((C_(max))_(TOP)) of the therapeutic agent in systemiccirculation versus time is at most about 10% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously((C_(max))_(IV)). In some other embodiments, the maximum plasmaconcentration ((C_(max))_(TOP)) of the therapeutic agent in systemiccirculation versus time is at most about 15% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously((C_(max))_(IV)). In some other embodiments, the maximum plasmaconcentration ((C_(max))_(TOP)) of the therapeutic agent in systemiccirculation versus time is at most about 20% of the AUC obtained whenthe same amount of the therapeutic agent is delivered intravenously((C_(max))_(IV)). In some embodiments, particularly when the C_(max) isdetermined from a plurality of subjects, the C_(max) is a mean C_(max)obtained from the plurality of subjects. Thus, in some furtherembodiments, (C_(max))_(TOP) or (C_(max))_(IV) may refer to a mean(C_(max))_(TOP) or mean (C_(max))_(IV), respectively. In some otherembodiments, an individual C_(max) value obtained for a single subjectmay be compared to a mean C_(max) obtained from a plurality of subjects.

In some embodiments, the topical administration provides a maximumplasma concentration ((C_(max))_(TOP)) of the therapeutic agent insystemic circulation versus time of about 0.1% to about 20%, forexample, at most about 1%, at most about 3%, at most about 5%, at mostabout 10%, at most about 15%, or at most about 20%, as that obtainedwhen the same amount of the therapeutic agent is deliveredsubcutaneously (to the same subject, or to a population of subjects)((C_(max))_(SC)). In some embodiments, the same amount of therapeuticagent is an approved or commercially-available dose. In some moreparticular embodiments, the maximum plasma concentration((C_(max))_(TOP)) of the therapeutic agent in systemic circulationversus time is at most about 1% of the AUC obtained when the same amountof the therapeutic agent is delivered subcutaneously ((C_(max))_(SC)).In some other embodiments, the maximum plasma concentration((C_(max))_(TOP)) of the therapeutic agent in systemic circulationversus time is at most about 3% of the AUC obtained when the same amountof the therapeutic agent is delivered subcutaneously ((C_(max))_(SC)).In some other embodiments, the maximum plasma concentration((C_(max))_(TOP)) of the therapeutic agent in systemic circulationversus time is at most about 5% of the AUC obtained when the same amountof the therapeutic agent is delivered subcutaneously ((C_(max))_(SC)).In some other embodiments, the maximum plasma concentration((C_(max))_(TOP)) of the therapeutic agent in systemic circulationversus time is at most about 10% of the AUC obtained when the sameamount of the therapeutic agent is delivered subcutaneously((C_(max))_(SC)). In some other embodiments, the maximum plasmaconcentration ((C_(max))_(TOP)) of the therapeutic agent in systemiccirculation versus time is at most about 15% of the AUC obtained whenthe same amount of the therapeutic agent is delivered subcutaneously((C_(max))_(SC)). In some other embodiments, the maximum plasmaconcentration ((C_(max))_(TOP)) of the therapeutic agent in systemiccirculation versus time is at most about 20% of the AUC obtained whenthe same amount of the therapeutic agent is delivered subcutaneously((C_(max))_(SC)). In some embodiments, particularly when the C_(max) isdetermined from a plurality of subjects, the C_(max) is a mean C_(max)obtained from the plurality of subjects. Thus, in some furtherembodiments, (C_(max))_(TOP) or (C_(max))_(SC) may refer to a mean(C_(max))_(TOP) or mean (C_(max))_(SC), respectively. In some otherembodiments, an individual C_(max) value obtained for a single subjectmay be compared to a mean C_(max) obtained from a plurality of subjects.

Diseases of the Endoderm

Also provided herein is a method of treating a disease or condition thatarises in a tissue originating from the endoderm of a subject. In someembodiments, the method comprises: releasing a pharmaceuticalformulation containing a therapeutically effective amount of atherapeutic agent from an ingestible device as disclosed herein to thegastrointestinal tract of a subject. In some embodiments, thepharmaceutical formulation is released with sufficient power, pressureand/or force for trans-epithelial delivery of the therapeutic agent tothe gastrointestinal tract. In some embodiments, the pharmaceuticalformulation is released with sufficient power, pressure and/or force forepithelial delivery of the therapeutic agent to the gastrointestinaltract. In some embodiments, the pharmaceutical formulation is releasedwith sufficient power, pressure and/or force for topical delivery of thetherapeutic agent to the gastrointestinal tract.

In some embodiments of the methods described herein, the tissueoriginating from the endoderm is selected from the group of: thestomach, the colon, the liver, the pancreas, the urinary bladder, theepithelial parts of the trachea, the lungs, the pharynx, the thyroid,the parathyroid, the intestines, and the gallbladder. In someembodiments of any of the methods described herein, the disease orcondition that arises in a tissue originating from the endoderm isselected from the group of: gastritis, Celiac disease, hepatitis,alcoholic lever disease, fatty liver disease (hepatic steatosis),non-alcoholic fatty liver disease (NASH), cirrhosis, primary schlerosingcholangitis, pancreatitis, insterstitial cystitits, asthma, chronicobstructic pulmonary disease, pulmonary fibrosis, pharyngitis,thyroiditis, hyperthyroidism, parathyroiditis, nephritis, Hashimoto'sdisease, Addison's disease, Graves' disease, Sjögren syndrome, type 1diabetes, pelvic inflammatory disease, auditory canal inflammation,tinnitus, vestibular neuritis, otitis media, auditory canalinflammation, tracheitis, cholestatic liver disease, primary biliarysclerosis, liver parenchyma, an inherited metabolic disorder of theliver, Byler syndrome, cerebrotendinous, xanthomatosis, Zellweger'ssyndrome, neonatal hepatitis, cystic fibrosis, ALGS (Alagillessyndrome), PFIC (progressive familial intrahepatic cholestasis),autoimmune hepatitis, primary biliary cirrhosis (PBC), liver fibrosis,NAFLD, portal hypertension, general cholestasis, such as in jaundice dueto drugs or during pregnancy, intra- and extrahepatic cholestasis, suchas hereditary forms of cholestasis, such as PFIC1, gall stones andcholedocholithiasis, malignancy causing obstruction of the biliary tree,symptoms (scratching, pruritus) due to cholestasis/jaundice, chronicautoimmune liver disease leading to progressive cholestasis, andpruritus of cholestatic liver disease, duodenal ulcers, enteritis(radiation-, chemotherapy-, or infection-induced enteritis),diverticulitis, pouchitis, cholecystitis, and cholangitis. In someembodiments of any of the methods described herein, the inflammatorydisease or condition that arises in a tissue originating from theendoderm is inflammation of the liver.

In some embodiments, the disease or condition that arises in a tissueoriginating from the endoderm is a disease or condition related to thegut-brain axis. In some embodiments, the disease or condition isselected from the group consisting of multiple sclerosis, Parkinson'sdisease, mild cognitive impairment, Alzheimer's, disease, encephalitis,and hepatic encephalopathy.

Administration of Additional Therapeutic Agents

Some embodiments of the methods described herein further includeadministering a one or more additional therapeutic agents. In someembodiments, the additional therapeutic agent is administered orally,intravenously or subcutaneously, where the additional therapeutic agentis the same therapeutic agent; a different therapeutic agent; or anagent having the same or a different biological target from thetherapeutic agent. In some embodiments of the methods described herein,the therapeutic agent is administered prior to the additionaltherapeutic agent. In some embodiments of the methods described herein,the therapeutic agent is administered after the additional therapeuticagent. In some embodiments of the methods described herein, thetherapeutic agent and the additional therapeutic agent are administeredsubstantially at the same time. In some embodiments of the methodsdescribed herein, the additional therapeutic agent is administeredorally. In some embodiments of the methods described herein, theadditional therapeutic agent is administered intravenously. In someembodiments of the methods described herein, the additional therapeuticagent is administered subcutaneously. In some embodiments of the methodsdescribed herein, the amount of the additional therapeutic agent whenadministered alone is less than the amount of the additional therapeuticagent when the therapeutic agent and the additional therapeutic agentare both administered systemically. In some embodiments of the methodsdescribed herein, the method does not include administering anadditional therapeutic agent.

Exemplary Conditions or Diseases

The presently described devices and methods can be used to treatnumerous conditions and diseases. In some embodiments, the conditionsand diseases are inflammatory and immune conditions and diseases.Exemplary inflammatory and immune conditions and diseases include, butare not limited to allergy, asthma, autoimmune diseases, coeliacdisease, glomerulonephritis, chronic peptic ulcer, tuberculosis,rheumatoid arthritis, juvenile rheumatoid arthritis, spondylarthritis,psoriasis, psoriatic arthritis, hidradenitis suppurativa, pyodermagangrenosum, ankylosing spondylitis, periodontitis, ulcerative colitisand Crohn's disease, sinusitis, active hepatitis, non-alcoholic fattyliver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liverfibrosis, liver cirrhosis, alcoholic fatty liver disease, alcoholichepatitis, alcoholic liver disease, systemic lupus erythematosus (SLE,Lupus), preperfusion injury, multiple sclerosis (MS), transplantrejection, graft versus host disease, dermatomyositis, interstitial lungdisease, lupus nephritis, motor neurone disease, osteoarthritis,myasthenia gravis, polymyositis, cholecystitis, scleroderma, Sjoegrenssyndrome, and Wegener granulomatosis. In some embodiments, theinflammatory and immune conditions and disease is selected from thegroup consisting of rheumatoid arthritis, psoriasis, psoriaticarthritis, ankylosing spondylitis, ulcerative colitis and Crohn'sdisease, non-alcoholic fatty liver disease (NAFLD), non-alcoholicsteatohepatitis (NASH), liver fibrosis, liver cirrhosis.

In some embodiments, the conditions and diseases are metabolic,endocrine and cardiovascular conditions and diseases. Exemplarymetabolic, endocrine and cardiovascular conditions and diseases include,but are not limited to diabetes mellitus, insulin dependent diabetes,obesity, obstructive sleep apnea, NAFLD, NASH, liver fibrosis, livercirrhosis, hypertension, pulmonary artery hypertension, primarysclerosing cholangitis, hyperlipidemia, hyperlipoproteinemia type I,lipodystrophy, acromegaly, myocardial infarction, and thromboembolism.In some embodiments, the metabolic, endocrine and cardiovascularconditions and diseases are selected from the group consisting ofdiabetes mellitus, obesity, NAFLD, NASH, liver fibrosis, livercirrhosis, and acromegaly.

In some embodiments, the conditions and diseases are hematologicconditions and diseases. Exemplary hematologic conditions and diseasesinclude, but are not limited to hemophilia, Factor VIII deficiency,Factor IX deficiency, Von Willebrands disease, Sickle cell anemia, Irondeficiency anemia, Neurology/Psychiatric, and Parkinsons disease. Insome embodiments, the hematologic condition is hemophilia.

In some embodiments, the conditions and diseases are musculoskeletalconditions and diseases. Exemplary musculoskeletal conditions anddiseases include, but are not limited to bone resorption; joint injury;male osteoporosis; osteogenesis imperfecta; osteoporosis; andpostmenopausal osteoporosis.

In some embodiments, the conditions and diseases are infections.Exemplary infections include, but are not limited to, bacterialinfection, bacterial meningitis, bacterial respiratory tract infection,bacterial urinary tract infection, bone and joint infection,cholangitis, complicated skin and skin structure infection, Neisseriagonorrhoeae infection, peritonitis, sepsis, abdominal abscess,Aspergillus infection, Candida infection, fungal infection,Acinetobacter infection, appendicitis, Escherichia coli infection,febrile neutropenia, Haemophilus influenzae infection; Klebsiellapneumoniae infection; lower respiratory tract infection; and pelvicinflammatory disease. In some embodiments, the conditions and diseasesare infections selected from the group consisting of bacterialinfections and sepsis.

In some embodiments, the conditions and diseases are respiratoryconditions and diseases. Exemplary respiratory conditions and diseasesinclude, but are not limited to, idiopathic pulmonary fibrosis.

In some embodiments, the conditions and diseases are cancers. Exemplarycancers include, but are not limited to acute myelogenous leukemia; analtumor; niliary cancer; bladder cancer; bone tumor; breast tumor; centralnervous system tumor; chronic lymphocytic leukemia; chronic myelocyticleukemia; diffuse large B-cell lymphoma; endometrioid carcinoma;esophagus tumor; fallopian tube cancer; follicle center lymphoma; germcell and embryonic cancer; glioblastoma; gonad tumor; head and necktumor; hematological neoplasm; hepatitis C virus infection;hepatocellular carcinoma; Hodgkins disease; hormone dependent prostatecancer; Kaposis sarcoma; leukoplakia; liver tumor; melanoma; Merkel cellcarcinoma; mesothelioma; metastatic bladder cancer; metastatic breastcancer; metastatic esophageal cancer; metastatic head and neck cancer;metastatic liver cancer; metastatic non-small cell lung cancer;metastatic ovary cancer; metastatic pancreas cancer; metastatic prostatecancer; metastatic renal cancer; metastatic renal cell carcinoma;metastatic stomach cancer; mouth tumor; multiple myeloma;myelodysplastic syndrome; neoplastic meningitis; non-Hodgkin lymphoma;non-small-cell lung cancer; ocular melanoma; osteosarcoma; ovary tumor;pancreas tumor; pancreatic ductal adenocarcinoma; peritoneal tumor;prostate tumor; rectal tumor; renal cell carcinoma; salivary glandcancer; sepsis; small-cell lung cancer; soft tissue sarcoma; solidtumor; squamous cell carcinoma; stage III melanoma; stage IV melanoma;stomach tumor; gestis tumor; uterine cervix tumor; uterus tumor; uvealmelanoma. In some embodiments, the cancer is selected from the groupconsisting of leukemia, lymphoma, hepatocellular carcinoma andmetastatic cancer.

Inflammatory Conditions or Diseases

In some embodiments, the condition or disease that can be treated withthe methods and devices disclosed herein is an inflammatory condition ordisease. The presently described devices and methods are based, in part,on the unexpected discovery that administration of an immune modulatorinto the tissue of a subject's gastrointestinal tract can result in theobservation of pharmacodynamics effects in tissues beyond the site ofdeposition. For example, an immune modulator administered into thetissue (e.g., mucosa or submucosa) of a subject's gastrointestinal tractcan result in one or more of the following: changes in anatomicalfeatures, including suppressed or reduced development, aggregation, oraccumulation of one or more of intestinal lymphoid tissues, isolatedlymphoid follicles (ILFs), or intestinal lymphoid aggregates; suppressedimmune response, including fewer T cells measured in lymph nodes orlymph tissues (which results in greater T cells forced into circulation,i.e., blood); decreased differentiation of immune cells (e.g., asmeasured using histology or through the use of a sampling device, orusing a sampling device); a decreased level of inflammatory cytokinelevels (e.g., as measured using biopsy or through the use of a samplingdevice); decreased endoscopic scoring; and improved efficacy oftreatment for IBD (e.g., using any of the clinical assessments of atreatment for IBD described herein) or other inflammatory conditions ofthe GI tract or endoderm (e.g., in the liver).

In some embodiments, the presently described devices provide for ahigher concentration of α4β7 expressing cells in the periphery (e.g.,blood) when an immune modulator is delivered into the GI tissue (e.g.,mucosa or submucosa) of one or more parts of the GI tract distal to thestomach (e.g., the small or large intestine) as compared to when thesame dose of the immune modulator is orally (without a device),intravenously, or subcutaneously administered. The presently describeddevices can, e.g., result in trafficked cells being forced out of thelocal gastrointestinal tissue (including the mucosa) and lymph system,and back into systemic circulation of a subject.

Accordingly, also provided herein are methods of treating a disease orcondition that arises in a tissue originating from the endoderm. Theendoderm forms the gastrointestinal tract, respiratory tract, endocrineglands, and organs, the auditory system and urinary system. Thus, thepresent disclosure includes compositions and devices for treatingdiseases and conditions found in the following tissues that originatefrom the endoderm (e.g., the stomach, the colon, the liver, thepancreas, the urinary bladder, the epithelial parts of the trachea, thelungs, the pharynx, the thyroid, the parathyroid, the intestines, andthe gallbladder). Also provided herein are methods of treating a diseaseor a condition that arises in a tissue originating from the endoderm(e.g., any of the exemplary diseases or conditions that arise in atissue originating from the endoderm described herein) that includedepositing one or more immune modulators into the tissue of the smallintestine using any of the devices or compositions described herein. Ina preferred embodiment, the compositions, devices and methods are fortreating inflammatory diseases and conditions found in the liver (e.g.,NAFLD, NASH, or cirrhosis).

Non-limiting examples of an inflammatory disease or condition thatarises in a tissue originating from the endoderm includes gastritis,celiac disease, hepatitis, alcoholic lever disease, fatty liver disease(hepatic steatosis), non-alcoholic fatty liver disease (NASH),cirrhosis, primary schlerosing cholangitis, pancreatitis, insterstitialcystitits, asthma, chronic obstructic pulmonary disease, pulmonaryfibrosis, pharyngitis, thyroiditis, hyperthyroidism, parathyroiditis,nephritis, Hashimoto's disease, Addison's disease, Graves' disease,Sjögren syndrome, type 1 diabetes, pelvic inflammatory disease, auditorycanal inflammation, tinnitus, vestibular neuritis, otitis media,auditory canal inflammation, tracheitis, cholestatic liver disease,primary biliary schlerosis, liver parenchyma, an inherited metabolicdisorder of the liver, Byler syndrome, cerebrotendinous, xanthomatosis,Zellweger's syndrome, neonatal hepatitis, cystic fibrosis, ALGS(Alagilles syndrome), PFIC (progressive familial intrahepaticcholestasis), autoimmune hepatitis, primary biliary cirrhosis (PBC),liver fibrosis, NAFLD, portal hypertension, general cholestasis, such asin jaundice due to drugs or during pregnancy, intra- and extrahepaticcholestasis, such as hereditary forms of cholestasis, such as PFIC1,gall stones and choledocholithiasis, malignancy causing obstruction ofthe biliary tree, symptoms (scratching, pruritus) due tocholestasis/jaundice, chronic autoimmune liver disease leading toprogressive cholestasis, and pruritus of cholestatic liver disease,duodenal ulcers, enteritis (radiation-, chemotherapy-, orinfection-induced enteritis), diverticulitis, pouchitis, cholecystitis,and cholangitis. Additional examples of diseases and conditions thatarise in a tissue originating from the endoderm are known in the art.

In some embodiments of any of the devices or methods described herein,the methods result in the introduction of the immune modulator to one ormore of the following, or the PD effects of the immune modulator (e.g.,any of the PD effects of immune modulators described herein) aredetectable in one or more of the following: throughout or in part of theparaaortic lymph nodes, throughout or in part of the MALT, throughout orin part of the GALT, throughout or in part of the inferior and superiormesenteric lymph nodes, and in one or more sections or subsections ofthe subject's gastrointestinal tract that is different than the sectionor subsection of the subject's gastrointestinal tract where the immunemodulator is released. In some embodiments of any of the devices ormethods described herein, the devices or methods result in the presenceor accumulation of the immune modulator in tissues or organs of theendoderm (e.g., the liver) at higher doses as compared to administrationof the immune modulator orally (without a device), intravenously, orsubcutaneously.

In some embodiments of any of the methods described herein, the methodsdo not result in (or do not result in a significant effect in)pharmacodynamics effect(s) (e.g., any of the clinical effects ormeasurements of an immune modulator described herein) outside of theparaaortic lymph nodes.

In some embodiments of any of the methods described herein, the methodsdo not result in (or do not result in a significant effect in)pharmacodynamics effect(s) (e.g., any of the clinical effects ormeasurements of an immune modulator described herein) outside of theMALT.

In some embodiments of any of the methods described herein, the methodsdo not result in (or do not result in a significant effect in)pharmacodynamics effect(s) (e.g., any of the clinical effects ormeasurements of an immune modulator described herein) outside of theGALT.

In any of the methods described herein, the subject can be any mammal(e.g., an animal model of any of the diseases described herein).

In some embodiments of any of the methods described herein, the methodresults in the suppression of the subject's immune response in one ormore of the paraaortic lymph nodes.

In some embodiments of any of the methods described herein, the methodresults in the suppression of the subject's immune response inmucosa-associated lymphoid tissue (MALT).

In some embodiments of any of the methods described herein, the methodresults in the suppression of the subject's immune response throughoutor in part of the gut-associated lymphoid tissue (GALT). For example, insome embodiments of any of the methods described herein, the methodresults in a reduction of T cells (e.g., any of the T cells describedherein, e.g., memory T cells) in Peyer's patches and/or mesenteric lymphnodes found in the GALT. In some embodiments of any of the methodsdescribed herein, the method results in a decreased level of T cells(e.g., any of the types of T cells described herein or known in the art)in a section or subsection of the subject's gastrointestinal tract thatis different than the section or subsection of the subject'sgastrointestinal tract where the immune modulator is released.

In some embodiments of any of the methods described herein, the methodresults in the suppression or reduction in the development, theaggregation, or accumulation of one or more of intestinal lymphoidtissues, isolated lymphoid follicles (ILFs), or intestinal lymphoidaggregates in mucosa-associated lymphoid tissue (MALT). In someembodiments of any of the methods described herein, the method resultsin the suppression of the development of one or more of intestinallymphoid tissues, isolated lymphoid follicles, or intestinal lymphoidaggregates in gut-associated lymphoid tissue (GALT). In some embodimentsof any of the methods described herein, the method results in thesuppression of the immune response in one or more sections orsubsections of the subject's gastrointestinal tract that is differentthan the section or subsection of the subject's gastrointestinal tractwhere the drug is released.

In some embodiments of any of the methods described herein, the methodsresult in pharmacodynamics effects proximal (“upstream”) to the site ofdisease in the subject. For example, in some embodiments of any of themethods described herein, the immune modulator is deposited in thetissue of the small intestine (e.g., duodenum or jejunum), butpharmacodynamics effects of the immune modulator are observed in theliver. In some embodiments of any of the methods described herein, theimmune modulator is deposited in the tissue of the small intestine(e.g., the duodenum or jejunum) and immune suppression is observedthroughout the mesenteric lymph system and other systems of theparaaortic lymph nodes, including the hepatic lymph nodes of the celiacgroup of the preaortic lymph nodes (preaortic lymph nodes are part ofthe paraaortic lymph nodes). In some embodiments of any of the methodsdescribed herein, the immune modulator is deposited in the smallintestine (e.g., duodenum, jejunum, or ileum) or colon (e.g., ascendingcolon, transverse colon, descending colon, rectum, or cecum), butpharmacodynamics effects of the immune modulator are throughout or inpart of the MALT, GALT, Peyer's patches, mesenteric lymph nodes,paraaortic lymph nodes, or any of the other tissues originating from theendoderm described herein or known in the art, in the mammal.

In some embodiments of any of the methods described herein, the methodresults in a decreased level or a decreased level of activation of oneor more of the following immune cells that participate in mucosal immuneresponse in a mammal: microfold cells (M cells), antigen-presentingcells (e.g., B-lymphocytes, dendritic cells, and macrophages), andeffector cells (e.g., T-lymphocytes).

Microfold cells (M cells) are found in the gut-associated lymphoidtissue (GALT) of the Peyer's patches in the small intestine. M cellsallow for the transport of microbes and particles across the epithelialcell layer from the gut lumen to the lamina propria where interactionswith immune cells can take place. M cells provide for the initiation ofmucosal immunity responses on the apical membrane by delivering antigensto antigen-presenting cells.

Antigen-presenting cells (APCs) include B-lymphocytes, dendritic cells,and macrophages. B-lymphocytes, also called B-cells, can internalizeantigen that binds to their B-cell receptor. Dendritic cells have thebroadest range of antigen presentation and are necessary for activationof naïve T cells. Dendritic cells present antigen to both helper andcytotoxic T cells. Macrophages can be stimulated by T-cell secretion ofinterferon gamma. After this activation, macrophages are able to expressmajor histocompatibility complex (MEW) class II and co-stimulatorymolecules, and can present phagocytosed peptide fragments to helper Tcells. The activation of macrophages can assist pathogen-infectedmacrophages in clearing the infection.

MHCs bind antigens derived from pathogens and display them on the cellsurface for recognition by appropriate T-cells. WIC class I presentsantigens from intracellular pathogens, such as viruses and bacteria. MHCclass II presents antigens from phagocytosed/pinocytosed pathogens.

Effector cells, as used herein, include T-lymphocytes, including CD4⁺(also called helper T cells), CD8⁺ (also called cytotoxic T cells),CD45Rb⁻ (more IL-10 and less TNFα in IBD) as compared with CD4⁺CD45Rb⁺,and CD44⁺ T cells. CD44 participates in lymphocytes activation,recirculation, and homing, and is an indicative marker for effectormemory T cells.

Exemplary Methods

Provided herein are methods of treating a disease or condition in asubject in need thereof. In some embodiments, the method includesadministering a dispensable substance to the gastrointestinal (GI) tractof the subject, where the administration includes orally administeringan ingestible device containing the dispensable substance to thesubject, where the dispensable substance contains a pharmaceuticalformulation including a therapeutically effective amount of atherapeutic agent, and releasing the dispensable substance from theingestible device as a jet to a desired location of the GI tract of thesubject, thereby directly delivering the dispensable substance to the GItract of the subject. In some embodiments, the administration istrans-epithelial. In some embodiments, the administration is epithelial.In some embodiments, the administration is topical.

In some embodiments, the direct delivery of the dispensable substance tothe submucosa and/or the mucosa (e.g., into the lamina propria) of thesubject provides systemic uptake of the therapeutic agent.

In some embodiments, the desired location of the GI tract is the smallintestine. In some embodiments, the desired location of the GI tract isone or more of the duodenum, the jejunum, and the ileum. In someembodiments, a portion of the dispensable substance is delivered to themucosa of the GI tract of the subject.

The disease or condition treatable by the methods provided herein can beany disease or condition described herein. In some embodiments, thedisease or condition is selected from an autoimmune disease orcondition, fibrosis, rheumatoid arthritis, non-alcoholic steatohepatitis(NASH), non-alcoholic fatty liver disease (NAFLD), an inflammatorydisease or disorder (e.g., inflammatory bowel disease (IBD)),hepatocellular carcinoma, a growth disorder (e.g., a growth hormonedeficiency or disorder (GHD)), an endocrine or metabolic disease orcondition (e.g., diabetes, insulin resistance, hyperglycemia,hyperlipidemia, obesity, hepatic steatosis, hyperinsulinemia,obstructive sleep apnea, liver fibrosis, liver cirrhosis, hypertension,pulmonary artery hypertension, primary sclerosing cholangitis,hyperlipoproteinemia type I, hypercholesterolemia, lipodystrophy,acromegaly, myocardial infarction, and thromboembolism), hemophilia(e.g., hemophilia A, hemophilia B, Von Willebrand disease), andcombinations thereof.

In some embodiments, the disease or condition is diabetes, for example,type I or type II diabetes. In some embodiments, the diabetes isselected from diabetes with Alzheimer's disease, diabetes with dementia,diabetes with Alzheimer's disease and dementia, diabetes with obesity,diabetes with NAFLD, diabetes with NASH, diabetes with NAFLD and NASH,and diabetes with a cardiovascular disease.

The therapeutic agent suitable for use in the methods described hereincan be any therapeutic agent disclosed herein. In some embodiments, thetherapeutic agent is a glucagon receptor agonist or a glucagon-likepeptide-1 (GLP-1) receptor agonist. In some embodiments, the therapeuticagent is a growth hormone. In some embodiments, the therapeutic agent isan insulin. In some embodiments, the therapeutic agent is a TNF-alphainhibitor. In some embodiments, the therapeutic agent is a peptide YYligand. In some embodiments, the therapeutic agent is an amylin analog.In some embodiments, the therapeutic agent is an alternative coagulationpromotor (ACP).

In some embodiments of the methods provided herein, the pharmaceuticalformulation is a fluid. In some embodiments, the pharmaceuticalformulation is a solution or suspension. In some embodiments, thepharmaceutical formulation has a viscosity of less than or equal to 10cP. In some embodiments, the pharmaceutical formulation has a viscosityof at least about 0.8 cP.

Particular Medical Approaches

Some embodiments of the invention relate to particular medicalapproaches, which use the ingestible device to deliver a particulartherapeutic agent, or class of agent, by a particular delivery mode totreat a particular disease, or class of disease. Particular medicalapproaches are disclosed in Table 18. All therapeutic agents disclosedin Table 18 optionally include the pharmaceutically acceptable salts andsolvates thereof in the case of small molecules, peptides, and nucleicacids, and the biosimilars thereof, and/or glycosylation variantsthereof, in the case of biologics such as antibodies, unless expresslyindicated otherwise.

TABLE 18 Particular medical approaches Approach Therapeutic agentDisease Delivery mode 1 GLP-1 receptor A disease or condition responsiveto Trans-epithelial agonist treatment with a GLP-1 receptor agonist 2GLP-1 receptor Metabolic or endocrine disorder Trans-epithelial agonist3 GLP-1 receptor Diabetes Trans-epithelial agonist 4 GLP-1 receptorDiabetes with Alzheimer's disease, Trans-epithelial agonist diabeteswith dementia, diabetes with Alzheimer's disease and dementia, diabeteswith obesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 5 GLP-1 receptor Aliver disease or disorder Trans-epithelial agonist 6 GLP-1 receptorCompensated liver cirrhosis Trans-epithelial agonist 7 GLP-1 receptorNon-alcoholic steatohepatitis (NASH) Trans-epithelial agonist ornon-alcoholic fatty liver disease (NAFLD) 8 GLP-1 receptor A bingeeating disorder Trans-epithelial agonist 9 GLP-1 receptor HyperglycemiaTrans-epithelial agonist 10 GLP-1 receptor Postprandial hyperglycemiaTrans-epithelial agonist 11 GLP-1 receptor Nicotine dependenceTrans-epithelial agonist 12 GLP-1 receptor A central nervous system(CNS) Trans-epithelial agonist disorder 13 GLP-1 receptor Alzheimer'sdisease or Parkinson's Trans-epithelial agonist disease 14 semaglutide Adisease or condition responsive to Trans-epithelial treatment with aGLP-1 receptor agonist 15 semaglutide Metabolic or endocrine disorderTrans-epithelial 16 semaglutide Diabetes Trans-epithelial 17 semaglutideDiabetes with Alzheimer's disease, Trans-epithelial diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 18 semaglutide Aliver disease or disorder Trans-epithelial 19 semaglutide Compensatedliver cirrhosis Trans-epithelial 20 semaglutide Non-alcoholicsteatohepatitis (NASH) Trans-epithelial or non-alcoholic fatty liverdisease (NAFLD) 21 semaglutide A binge eating disorder Trans-epithelial22 semaglutide Hyperglycemia Trans-epithelial 23 semaglutidePostprandial hyperglycemia Trans-epithelial 24 semaglutide Nicotinedependence Trans-epithelial 25 semaglutide A central nervous system(CNS) Trans-epithelial disorder 26 semaglutide Alzheimer's disease orParkinson's Trans-epithelial disease 27 dulaglutide A disease orcondition responsive to Trans-epithelial treatment with a GLP-1 receptoragonist 28 dulaglutide Metabolic or endocrine disorder Trans-epithelial29 dulaglutide Diabetes Trans-epithelial 30 dulaglutide Diabetes withAlzheimer's disease, Trans-epithelial diabetes with dementia, diabeteswith Alzheimer's disease and dementia, diabetes with obesity, diabeteswith non-alcoholic fatty liver disease (NAFLD), diabetes withnon-alcoholic steatohepatitis (NASH), diabetes with NAFLD and NASH, ordiabetes with a cardiovascular disease 31 dulaglutide A liver disease ordisorder Trans-epithelial 32 dulaglutide Compensated liver cirrhosisTrans-epithelial 33 dulaglutide Non-alcoholic steatohepatitis (NASH)Trans-epithelial or non-alcoholic fatty liver disease (NAFLD) 34dulaglutide A binge eating disorder Trans-epithelial 35 dulaglutideHyperglycemia Trans-epithelial 36 dulaglutide Postprandial hyperglycemiaTrans-epithelial 37 dulaglutide Nicotine dependence Trans-epithelial 38dulaglutide A central nervous system (CNS) Trans-epithelial disorder 39dulaglutide Alzheimer's disease or Parkinson's Trans-epithelial disease40 albiglutide A disease or condition responsive to Trans-epithelialtreatment with a GLP-1 receptor agonist 41 albiglutide Metabolic orendocrine disorder Trans-epithelial 42 albiglutide DiabetesTrans-epithelial 43 albiglutide Diabetes with Alzheimer's disease,Trans-epithelial diabetes with dementia, diabetes with Alzheimer'sdisease and dementia, diabetes with obesity, diabetes with non-alcoholicfatty liver disease (NAFLD), diabetes with non-alcoholic steatohepatitis(NASH), diabetes with NAFLD and NASH, or diabetes with a cardiovasculardisease 44 albiglutide A liver disease or disorder Trans-epithelial 45albiglutide Compensated liver cirrhosis Trans-epithelial 46 albiglutideNon-alcoholic steatohepatitis (NASH) Trans-epithelial or non-alcoholicfatty liver disease (NAFLD) 47 albiglutide A binge eating disorderTrans-epithelial 48 albiglutide Hyperglycemia Trans-epithelial 49albiglutide Postprandial hyperglycemia Trans-epithelial 50 albiglutideNicotine dependence Trans-epithelial 51 albiglutide A central nervoussystem (CNS) Trans-epithelial disorder 52 albiglutide Alzheimer'sdisease or Parkinson's Trans-epithelial disease 53 exenatide A diseaseor condition responsive to Trans-epithelial treatment with a GLP-1receptor agonist 54 exenatide Metabolic or endocrine disorderTrans-epithelial 55 exenatide Diabetes Trans-epithelial 56 exenatideDiabetes with Alzheimer's disease, Trans-epithelial diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 57 exenatide A liverdisease or disorder Trans-epithelial 58 exenatide Compensated livercirrhosis Trans-epithelial 59 exenatide Non-alcoholic steatohepatitis(NASH) Trans-epithelial or non-alcoholic fatty liver disease (NAFLD) 60exenatide A binge eating disorder Trans-epithelial 61 exenatideHyperglycemia Trans-epithelial 62 exenatide Postprandial hyperglycemiaTrans-epithelial 63 exenatide Nicotine dependence Trans-epithelial 64exenatide A central nervous system (CNS) Trans-epithelial disorder 65exenatide Alzheimer's disease or Parkinson's Trans-epithelial disease 66liraglutide A disease or condition responsive to Trans-epithelialtreatment with a GLP-1 receptor agonist 67 liraglutide Metabolic orendocrine disorder Trans-epithelial 68 liraglutide DiabetesTrans-epithelial 69 liraglutide Diabetes with Alzheimer's disease,Trans-epithelial diabetes with dementia, diabetes with Alzheimer'sdisease and dementia, diabetes with obesity, diabetes with non-alcoholicfatty liver disease (NAFLD), diabetes with non-alcoholic steatohepatitis(NASH), diabetes with NAFLD and NASH, or diabetes with a cardiovasculardisease 70 liraglutide A liver disease or disorder Trans-epithelial 71liraglutide Compensated liver cirrhosis Trans-epithelial 72 liraglutideNon-alcoholic steatohepatitis (NASH) Trans-epithelial or non-alcoholicfatty liver disease (NAFLD) 73 liraglutide A binge eating disorderTrans-epithelial 74 liraglutide Hyperglycemia Trans-epithelial 75liraglutide Postprandial hyperglycemia Trans-epithelial 76 liraglutideNicotine dependence Trans-epithelial 77 liraglutide A central nervoussystem (CNS) Trans-epithelial disorder 78 liraglutide Alzheimer'sdisease or Parkinson's Trans-epithelial disease 79 lixisenatide Adisease or condition responsive to Trans-epithelial treatment with aGLP-1 receptor agonist 80 lixisenatide Metabolic or endocrine disorderTrans-epithelial 81 lixisenatide Diabetes Trans-epithelial 82lixisenatide Diabetes with Alzheimer's disease, Trans-epithelialdiabetes with dementia, diabetes with Alzheimer's disease and dementia,diabetes with obesity, diabetes with non-alcoholic fatty liver disease(NAFLD), diabetes with non-alcoholic steatohepatitis (NASH), diabeteswith NAFLD and NASH, or diabetes with a cardiovascular disease 83lixisenatide A liver disease or disorder Trans-epithelial 84lixisenatide Compensated liver cirrhosis Trans-epithelial 85lixisenatide Non-alcoholic steatohepatitis (NASH) Trans-epithelial ornon-alcoholic fatty liver disease (NAFLD) 86 lixisenatide A binge eatingdisorder Trans-epithelial 87 lixisenatide Hyperglycemia Trans-epithelial88 lixisenatide Postprandial hyperglycemia Trans-epithelial 89lixisenatide Nicotine dependence Trans-epithelial 90 lixisenatide Acentral nervous system (CNS) Trans-epithelial disorder 91 lixisenatideAlzheimer's disease or Parkinson's Trans-epithelial disease 92NNC-0090-2746 A disease or condition responsive to Trans-epithelialtreatment with a GLP-1 receptor agonist 93 NNC-0090-2746 Metabolic orendocrine disorder Trans-epithelial 94 NNC-0090-2746 DiabetesTrans-epithelial 95 NNC-0090-2746 Diabetes with Alzheimer's disease,Trans-epithelial diabetes with dementia, diabetes with Alzheimer'sdisease and dementia, diabetes with obesity, diabetes with non-alcoholicfatty liver disease (NAFLD), diabetes with non-alcoholic steatohepatitis(NASH), diabetes with NAFLD and NASH, or diabetes with a cardiovasculardisease 96 NNC-0090-2746 A liver disease or disorder Trans-epithelial 97NNC-0090-2746 Compensated liver cirrhosis Trans-epithelial 98NNC-0090-2746 Non-alcoholic steatohepatitis (NASH) Trans-epithelial ornon-alcoholic fatty liver disease (NAFLD) 99 NNC-0090-2746 A bingeeating disorder Trans-epithelial 100 NNC-0090-2746 HyperglycemiaTrans-epithelial 101 NNC-0090-2746 Postprandial hyperglycemiaTrans-epithelial 102 NNC-0090-2746 Nicotine dependence Trans-epithelial103 NNC-0090-2746 A central nervous system (CNS) Trans-epithelialdisorder 104 NNC-0090-2746 Alzheimer's disease or Parkinson'sTrans-epithelial disease 105 glucagon A disease or condition responsiveto Trans-epithelial treatment with a GLP-1 receptor agonist 106 glucagonMetabolic or endocrine disorder Trans-epithelial 107 glucagon DiabetesTrans-epithelial 108 glucagon Diabetes with Alzheimer's disease,Trans-epithelial diabetes with dementia, diabetes with Alzheimer'sdisease and dementia, diabetes with obesity, diabetes with non-alcoholicfatty liver disease (NAFLD), diabetes with non-alcoholic steatohepatitis(NASH), diabetes with NAFLD and NASH, or diabetes with a cardiovasculardisease 109 glucagon A liver disease or disorder Trans-epithelial 110glucagon Compensated liver cirrhosis Trans-epithelial 111 glucagonNon-alcoholic steatohepatitis (NASH) Trans-epithelial or non-alcoholicfatty liver disease (NAFLD) 112 glucagon A binge eating disorderTrans-epithelial 113 glucagon Hyperglycemia Trans-epithelial 114glucagon Postprandial hyperglycemia Trans-epithelial 115 glucagonNicotine dependence Trans-epithelial 116 glucagon A central nervoussystem (CNS) Trans-epithelial disorder 117 glucagon Alzheimer's diseaseor Parkinson's Trans-epithelial disease 118 NN-9277 A disease orcondition responsive to Trans-epithelial treatment with a GLP-1 receptoragonist 119 NN-9277 Metabolic or endocrine disorder Trans-epithelial 120NN-9277 Diabetes Trans-epithelial 121 NN-9277 Diabetes with Alzheimer'sdisease, Trans-epithelial diabetes with dementia, diabetes withAlzheimer's disease and dementia, diabetes with obesity, diabetes withnon-alcoholic fatty liver disease (NAFLD), diabetes with non-alcoholicsteatohepatitis (NASH), diabetes with NAFLD and NASH, or diabetes with acardiovascular disease 122 NN-9277 A liver disease or disorderTrans-epithelial 123 NN-9277 Compensated liver cirrhosisTrans-epithelial 124 NN-9277 Non-alcoholic steatohepatitis (NASH)Trans-epithelial or non-alcoholic fatty liver disease (NAFLD) 125NN-9277 A binge eating disorder Trans-epithelial 126 NN-9277Hyperglycemia Trans-epithelial 127 NN-9277 Postprandial hyperglycemiaTrans-epithelial 128 NN-9277 Nicotine dependence Trans-epithelial 129NN-9277 A central nervous system (CNS) Trans-epithelial disorder 130NN-9277 Alzheimer's disease or Parkinson's Trans-epithelial disease 131NN-9423 A disease or condition responsive to Trans-epithelial treatmentwith a GLP-1 receptor agonist 132 NN-9423 Metabolic or endocrinedisorder Trans-epithelial 133 NN-9423 Diabetes Trans-epithelial 134NN-9423 Diabetes with Alzheimer's disease, Trans-epithelial diabeteswith dementia, diabetes with Alzheimer's disease and dementia, diabeteswith obesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 135 NN-9423 A liverdisease or disorder Trans-epithelial 136 NN-9423 Compensated livercirrhosis Trans-epithelial 137 NN-9423 Non-alcoholic steatohepatitis(NASH) Trans-epithelial or non-alcoholic fatty liver disease (NAFLD) 138NN-9423 A binge eating disorder Trans-epithelial 139 NN-9423Hyperglycemia Trans-epithelial 140 NN-9423 Postprandial hyperglycemiaTrans-epithelial 141 NN-9423 Nicotine dependence Trans-epithelial 142NN-9423 A central nervous system (CNS) Trans-epithelial disorder 143NN-9423 Alzheimer's disease or Parkinson's Trans-epithelial disease 144GLP-1 receptor A disease or condition responsive to Epithelial agonisttreatment with a GLP-1 receptor agonist 145 GLP-1 receptor Metabolic orendocrine disorder Epithelial agonist 146 GLP-1 receptor DiabetesEpithelial agonist 147 GLP-1 receptor Diabetes with Alzheimer's disease,Epithelial agonist diabetes with dementia, diabetes with Alzheimer'sdisease and dementia, diabetes with obesity, diabetes with non-alcoholicfatty liver disease (NAFLD), diabetes with non-alcoholic steatohepatitis(NASH), diabetes with NAFLD and NASH, or diabetes with a cardiovasculardisease 148 GLP-1 receptor A liver disease or disorder Epithelialagonist 149 GLP-1 receptor Compensated liver cirrhosis Epithelialagonist 150 GLP-1 receptor Non-alcoholic steatohepatitis (NASH)Epithelial agonist or non-alcoholic fatty liver disease (NAFLD) 151GLP-1 receptor A binge eating disorder Epithelial agonist 152 GLP-1receptor Hyperglycemia Epithelial agonist 153 GLP-1 receptorPostprandial hyperglycemia Epithelial agonist 154 GLP-1 receptorNicotine dependence Epithelial agonist 155 GLP-1 receptor A centralnervous system (CNS) Epithelial agonist disorder 156 GLP-1 receptorAlzheimer's disease or Parkinson's Epithelial agonist disease 157semaglutide A disease or condition responsive to Epithelial treatmentwith a GLP-1 receptor agonist 158 semaglutide Metabolic or endocrinedisorder Epithelial 159 semaglutide Diabetes Epithelial 160 semaglutideDiabetes with Alzheimer's disease, Epithelial diabetes with dementia,diabetes with Alzheimer's disease and dementia, diabetes with obesity,diabetes with non-alcoholic fatty liver disease (NAFLD), diabetes withnon-alcoholic steatohepatitis (NASH), diabetes with NAFLD and NASH, ordiabetes with a cardiovascular disease 161 semaglutide A liver diseaseor disorder Epithelial 162 semaglutide Compensated liver cirrhosisEpithelial 163 semaglutide Non-alcoholic steatohepatitis (NASH)Epithelial or non-alcoholic fatty liver disease (NAFLD) 164 semaglutideA binge eating disorder Epithelial 165 semaglutide HyperglycemiaEpithelial 166 semaglutide Postprandial hyperglycemia Epithelial 167semaglutide Nicotine dependence Epithelial 168 semaglutide A centralnervous system (CNS) Epithelial disorder 169 semaglutide Alzheimer'sdisease or Parkinson's Epithelial disease 170 dulaglutide A disease orcondition responsive to Epithelial treatment with a GLP-1 receptoragonist 171 dulaglutide Metabolic or endocrine disorder Epithelial 172dulaglutide Diabetes Epithelial 173 dulaglutide Diabetes withAlzheimer's disease, Epithelial diabetes with dementia, diabetes withAlzheimer's disease and dementia, diabetes with obesity, diabetes withnon-alcoholic fatty liver disease (NAFLD), diabetes with non-alcoholicsteatohepatitis (NASH), diabetes with NAFLD and NASH, or diabetes with acardiovascular disease 174 dulaglutide A liver disease or disorderEpithelial 175 dulaglutide Compensated liver cirrhosis Epithelial 176dulaglutide Non-alcoholic steatohepatitis (NASH) Epithelial ornon-alcoholic fatty liver disease (NAFLD) 177 dulaglutide A binge eatingdisorder Epithelial 178 dulaglutide Hyperglycemia Epithelial 179dulaglutide Postprandial hyperglycemia Epithelial 180 dulaglutideNicotine dependence Epithelial 181 dulaglutide A central nervous system(CNS) Epithelial disorder 182 dulaglutide Alzheimer's disease orParkinson's Epithelial disease 183 albiglutide A disease or conditionresponsive to Epithelial treatment with a GLP-1 receptor agonist 184albiglutide Metabolic or endocrine disorder Epithelial 185 albiglutideDiabetes Epithelial 186 albiglutide Diabetes with Alzheimer's disease,Epithelial diabetes with dementia, diabetes with Alzheimer's disease anddementia, diabetes with obesity, diabetes with non-alcoholic fatty liverdisease (NAFLD), diabetes with non-alcoholic steatohepatitis (NASH),diabetes with NAFLD and NASH, or diabetes with a cardiovascular disease187 albiglutide A liver disease or disorder Epithelial 188 albiglutideCompensated liver cirrhosis Epithelial 189 albiglutide Non-alcoholicsteatohepatitis (NASH) Epithelial or non-alcoholic fatty liver disease(NAFLD) 190 albiglutide A binge eating disorder Epithelial 191albiglutide Hyperglycemia Epithelial 192 albiglutide Postprandialhyperglycemia Epithelial 193 albiglutide Nicotine dependence Epithelial194 albiglutide A central nervous system (CNS) Epithelial disorder 195albiglutide Alzheimer's disease or Parkinson's Epithelial disease 196exenatide A disease or condition responsive to Epithelial treatment witha GLP-1 receptor agonist 197 exenatide Metabolic or endocrine disorderEpithelial 198 exenatide Diabetes Epithelial 199 exenatide Diabetes withAlzheimer's disease, Epithelial diabetes with dementia, diabetes withAlzheimer's disease and dementia, diabetes with obesity, diabetes withnon-alcoholic fatty liver disease (NAFLD), diabetes with non-alcoholicsteatohepatitis (NASH), diabetes with NAFLD and NASH, or diabetes with acardiovascular disease 200 exenatide A liver disease or disorderEpithelial 201 exenatide Compensated liver cirrhosis Epithelial 202exenatide Non-alcoholic steatohepatitis (NASH) Epithelial ornon-alcoholic fatty liver disease (NAFLD) 203 exenatide A binge eatingdisorder Epithelial 204 exenatide Hyperglycemia Epithelial 205 exenatidePostprandial hyperglycemia Epithelial 206 exenatide Nicotine dependenceEpithelial 207 exenatide A central nervous system (CNS) Epithelialdisorder 208 exenatide Alzheimer's disease or Parkinson's Epithelialdisease 209 liraglutide A disease or condition responsive to Epithelialtreatment with a GLP-1 receptor agonist 210 liraglutide Metabolic orendocrine disorder Epithelial 211 liraglutide Diabetes Epithelial 212liraglutide Diabetes with Alzheimer's disease, Epithelial diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 213 liraglutide Aliver disease or disorder Epithelial 214 liraglutide Compensated livercirrhosis Epithelial 215 liraglutide Non-alcoholic steatohepatitis(NASH) Epithelial or non-alcoholic fatty liver disease (NAFLD) 216liraglutide A binge eating disorder Epithelial 217 liraglutideHyperglycemia Epithelial 218 liraglutide Postprandial hyperglycemiaEpithelial 219 liraglutide Nicotine dependence Epithelial 220liraglutide A central nervous system (CNS) Epithelial disorder 221liraglutide Alzheimer's disease or Parkinson's Epithelial disease 222lixisenatide A disease or condition responsive to Epithelial treatmentwith a GLP-1 receptor agonist 223 lixisenatide Metabolic or endocrinedisorder Epithelial 224 lixisenatide Diabetes Epithelial 225lixisenatide Diabetes with Alzheimer's disease, Epithelial diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 226 lixisenatide Aliver disease or disorder Epithelial 227 lixisenatide Compensated livercirrhosis Epithelial 228 lixisenatide Non-alcoholic steatohepatitis(NASH) Epithelial or non-alcoholic fatty liver disease (NAFLD) 229lixisenatide A binge eating disorder Epithelial 230 lixisenatideHyperglycemia Epithelial 231 lixisenatide Postprandial hyperglycemiaEpithelial 232 lixisenatide Nicotine dependence Epithelial 233lixisenatide A central nervous system (CNS) Epithelial disorder 234lixisenatide Alzheimer's disease or Parkinson's Epithelial disease 235NNC-0090-2746 A disease or condition responsive to Epithelial treatmentwith a GLP-1 receptor agonist 236 NNC-0090-2746 Metabolic or endocrinedisorder Epithelial 237 NNC-0090-2746 Diabetes Epithelial 238NNC-0090-2746 Diabetes with Alzheimer's disease, Epithelial diabeteswith dementia, diabetes with Alzheimer's disease and dementia, diabeteswith obesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 239 NNC-0090-2746 Aliver disease or disorder Epithelial 240 NNC-0090-2746 Compensated livercirrhosis Epithelial 241 NNC-0090-2746 Non-alcoholic steatohepatitis(NASH) Epithelial or non-alcoholic fatty liver disease (NAFLD) 242NNC-0090-2746 A binge eating disorder Epithelial 243 NNC-0090-2746Hyperglycemia Epithelial 244 NNC-0090-2746 Postprandial hyperglycemiaEpithelial 245 NNC-0090-2746 Nicotine dependence Epithelial 246NNC-0090-2746 A central nervous system (CNS) Epithelial disorder 247NNC-0090-2746 Alzheimer's disease or Parkinson's Epithelial disease 248glucagon A disease or condition responsive to Epithelial treatment witha GLP-1 receptor agonist 249 glucagon Metabolic or endocrine disorderEpithelial 250 glucagon Diabetes Epithelial 251 glucagon Diabetes withAlzheimer's disease, Epithelial diabetes with dementia, diabetes withAlzheimer's disease and dementia, diabetes with obesity, diabetes withnon-alcoholic fatty liver disease (NAFLD), diabetes with non-alcoholicsteatohepatitis (NASH), diabetes with NAFLD and NASH, or diabetes with acardiovascular disease 252 glucagon A liver disease or disorderEpithelial 253 glucagon Compensated liver cirrhosis Epithelial 254glucagon Non-alcoholic steatohepatitis (NASH) Epithelial ornon-alcoholic fatty liver disease (NAFLD) 255 glucagon A binge eatingdisorder Epithelial 256 glucagon Hyperglycemia Epithelial 257 glucagonPostprandial hyperglycemia Epithelial 258 glucagon Nicotine dependenceEpithelial 259 glucagon A central nervous system (CNS) Epithelialdisorder 260 glucagon Alzheimer's disease or Parkinson's Epithelialdisease 261 NN-9277 A disease or condition responsive to Epithelialtreatment with a GLP-1 receptor agonist 262 NN-9277 Metabolic orendocrine disorder Epithelial 263 NN-9277 Diabetes Epithelial 264NN-9277 Diabetes with Alzheimer's disease, Epithelial diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 265 NN-9277 A liverdisease or disorder Epithelial 266 NN-9277 Compensated liver cirrhosisEpithelial 267 NN-9277 Non-alcoholic steatohepatitis (NASH) Epithelialor non-alcoholic fatty liver disease (NAFLD) 268 NN-9277 A binge eatingdisorder Epithelial 269 NN-9277 Hyperglycemia Epithelial 270 NN-9277Postprandial hyperglycemia Epithelial 271 NN-9277 Nicotine dependenceEpithelial 272 NN-9277 A central nervous system (CNS) Epithelialdisorder 273 NN-9277 Alzheimer's disease or Parkinson's Epithelialdisease 274 NN-9423 A disease or condition responsive to Epithelialtreatment with a GLP-1 receptor agonist 275 NN-9423 Metabolic orendocrine disorder Epithelial 276 NN-9423 Diabetes Epithelial 277NN-9423 Diabetes with Alzheimer's disease, Epithelial diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 278 NN-9423 A liverdisease or disorder Epithelial 279 NN-9423 Compensated liver cirrhosisEpithelial 280 NN-9423 Non-alcoholic steatohepatitis (NASH) Epithelialor non-alcoholic fatty liver disease (NAFLD) 281 NN-9423 A binge eatingdisorder Epithelial 282 NN-9423 Hyperglycemia Epithelial 283 NN-9423Postprandial hyperglycemia Epithelial 284 NN-9423 Nicotine dependenceEpithelial 285 NN-9423 A central nervous system (CNS) Epithelialdisorder 286 NN-9423 Alzheimer's disease or Parkinson's Epithelialdisease 287 GLP-1 receptor A disease or condition responsive to Topicalagonist treatment with a GLP-1 receptor agonist 288 GLP-1 receptorMetabolic or endocrine disorder Topical agonist 289 GLP-1 receptorDiabetes Topical agonist 290 GLP-1 receptor Diabetes with Alzheimer'sdisease, Topical agonist diabetes with dementia, diabetes withAlzheimer's disease and dementia, diabetes with obesity, diabetes withnon-alcoholic fatty liver disease (NAFLD), diabetes with non-alcoholicsteatohepatitis (NASH), diabetes with NAFLD and NASH, or diabetes with acardiovascular disease 291 GLP-1 receptor A liver disease or disorderTopical agonist 292 GLP-1 receptor Compensated liver cirrhosis Topicalagonist 293 GLP-1 receptor Non-alcoholic steatohepatitis (NASH) Topicalagonist or non-alcoholic fatty liver disease (NAFLD) 294 GLP-1 receptorA binge eating disorder Topical agonist 295 GLP-1 receptor HyperglycemiaTopical agonist 296 GLP-1 receptor Postprandial hyperglycemia Topicalagonist 297 GLP-1 receptor Nicotine dependence Topical agonist 298 GLP-1receptor A central nervous system (CNS) Topical agonist disorder 299GLP-1 receptor Alzheimer's disease or Parkinson's Topical agonistdisease 300 semaglutide A disease or condition responsive to Topicaltreatment with a GLP-1 receptor agonist 301 semaglutide Metabolic orendocrine disorder Topical 302 semaglutide Diabetes Topical 303semaglutide Diabetes with Alzheimer's disease, Topical diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 304 semaglutide Aliver disease or disorder Topical 305 semaglutide Compensated livercirrhosis Topical 306 semaglutide Non-alcoholic steatohepatitis (NASH)Topical or non-alcoholic fatty liver disease (NAFLD) 307 semaglutide Abinge eating disorder Topical 308 semaglutide Hyperglycemia Topical 309semaglutide Postprandial hyperglycemia Topical 310 semaglutide Nicotinedependence Topical 311 semaglutide A central nervous system (CNS)Topical disorder 312 semaglutide Alzheimer's disease or Parkinson'sTopical disease 313 dulaglutide A disease or condition responsive toTopical treatment with a GLP-1 receptor agonist 314 dulaglutideMetabolic or endocrine disorder Topical 315 dulaglutide Diabetes Topical316 dulaglutide Diabetes with Alzheimer's disease, Topical diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 317 dulaglutide Aliver disease or disorder Topical 318 dulaglutide Compensated livercirrhosis Topical 319 dulaglutide Non-alcoholic steatohepatitis (NASH)Topical or non-alcoholic fatty liver disease (NAFLD) 320 dulaglutide Abinge eating disorder Topical 321 dulaglutide Hyperglycemia Topical 322dulaglutide Postprandial hyperglycemia Topical 323 dulaglutide Nicotinedependence Topical 324 dulaglutide A central nervous system (CNS)Topical disorder 325 dulaglutide Alzheimer's disease or Parkinson'sTopical disease 326 albiglutide A disease or condition responsive toTopical treatment with a GLP-1 receptor agonist 327 albiglutideMetabolic or endocrine disorder Topical 328 albiglutide Diabetes Topical329 albiglutide Diabetes with Alzheimer's disease, Topical diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 330 albiglutide Aliver disease or disorder Topical 331 albiglutide Compensated livercirrhosis Topical 332 albiglutide Non-alcoholic steatohepatitis (NASH)Topical or non-alcoholic fatty liver disease (NAFLD) 333 albiglutide Abinge eating disorder Topical 334 albiglutide Hyperglycemia Topical 335albiglutide Postprandial hyperglycemia Topical 336 albiglutide Nicotinedependence Topical 337 albiglutide A central nervous system (CNS)Topical disorder 338 albiglutide Alzheimer's disease or Parkinson'sTopical disease 339 exenatide A disease or condition responsive toTopical treatment with a GLP-1 receptor agonist 340 exenatide Metabolicor endocrine disorder Topical 341 exenatide Diabetes Topical 342exenatide Diabetes with Alzheimer's disease, Topical diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 343 exenatide Aliver disease or disorder Topical 344 exenatide Compensated livercirrhosis Topical 345 exenatide Non-alcoholic steatohepatitis (NASH)Topical or non-alcoholic fatty liver disease (NAFLD) 346 exenatide Abinge eating disorder Topical 347 exenatide Hyperglycemia Topical 348exenatide Postprandial hyperglycemia Topical 349 exenatide Nicotinedependence Topical 350 exenatide A central nervous system (CNS) Topicaldisorder 351 exenatide Alzheimer's disease or Parkinson's Topicaldisease 352 liraglutide A disease or condition responsive to Topicaltreatment with a GLP-1 receptor agonist 353 liraglutide Metabolic orendocrine disorder Topical 354 liraglutide Diabetes Topical 355liraglutide Diabetes with Alzheimer's disease, Topical diabetes withdementia, diabetes with Alzheimer's disease and dementia, diabetes withobesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 356 liraglutide Aliver disease or disorder Topical 357 liraglutide Compensated livercirrhosis Topical 358 liraglutide Non-alcoholic steatohepatitis (NASH)Topical or non-alcoholic fatty liver disease (NAFLD) 359 liraglutide Abinge eating disorder Topical 360 liraglutide Hyperglycemia Topical 361liraglutide Postprandial hyperglycemia Topical 362 liraglutide Nicotinedependence Topical 363 liraglutide A central nervous system (CNS)Topical disorder 364 liraglutide Alzheimer's disease or Parkinson'sTopical disease 365 lixisenatide A disease or condition responsive toTopical treatment with a GLP-1 receptor agonist 366 lixisenatideMetabolic or endocrine disorder Topical 367 lixisenatide DiabetesTopical 368 lixisenatide Diabetes with Alzheimer's disease, Topicaldiabetes with dementia, diabetes with Alzheimer's disease and dementia,diabetes with obesity, diabetes with non-alcoholic fatty liver disease(NAFLD), diabetes with non-alcoholic steatohepatitis (NASH), diabeteswith NAFLD and NASH, or diabetes with a cardiovascular disease 369lixisenatide A liver disease or disorder Topical 370 lixisenatideCompensated liver cirrhosis Topical 371 lixisenatide Non-alcoholicsteatohepatitis (NASH) Topical or non-alcoholic fatty liver disease(NAFLD) 372 lixisenatide A binge eating disorder Topical 373lixisenatide Hyperglycemia Topical 374 lixisenatide Postprandialhyperglycemia Topical 375 lixisenatide Nicotine dependence Topical 376lixisenatide A central nervous system (CNS) Topical disorder 377lixisenatide Alzheimer's disease or Parkinson's Topical disease 378NNC-0090-2746 A disease or condition responsive to Topical treatmentwith a GLP-1 receptor agonist 379 NNC-0090-2746 Metabolic or endocrinedisorder Topical 380 NNC-0090-2746 Diabetes Topical 381 NNC-0090-2746Diabetes with Alzheimer's disease, Topical diabetes with dementia,diabetes with Alzheimer's disease and dementia, diabetes with obesity,diabetes with non-alcoholic fatty liver disease (NAFLD), diabetes withnon-alcoholic steatohepatitis (NASH), diabetes with NAFLD and NASH, ordiabetes with a cardiovascular disease 382 NNC-0090-2746 A liver diseaseor disorder Topical 383 NNC-0090-2746 Compensated liver cirrhosisTopical 384 NNC-0090-2746 Non-alcoholic steatohepatitis (NASH) Topicalor non-alcoholic fatty liver disease (NAFLD) 385 NNC-0090-2746 A bingeeating disorder Topical 386 NNC-0090-2746 Hyperglycemia Topical 387NNC-0090-2746 Postprandial hyperglycemia Topical 388 NNC-0090-2746Nicotine dependence Topical 389 NNC-0090-2746 A central nervous system(CNS) Topical disorder 390 NNC-0090-2746 Alzheimer's disease orParkinson's Topical disease 391 glucagon A disease or conditionresponsive to Topical treatment with a GLP-1 receptor agonist 392glucagon Metabolic or endocrine disorder Topical 393 glucagon DiabetesTopical 394 glucagon Diabetes with Alzheimer's disease, Topical diabeteswith dementia, diabetes with Alzheimer's disease and dementia, diabeteswith obesity, diabetes with non-alcoholic fatty liver disease (NAFLD),diabetes with non-alcoholic steatohepatitis (NASH), diabetes with NAFLDand NASH, or diabetes with a cardiovascular disease 395 glucagon A liverdisease or disorder Topical 396 glucagon Compensated liver cirrhosisTopical 397 glucagon Non-alcoholic steatohepatitis (NASH) Topical ornon-alcoholic fatty liver disease (NAFLD) 398 glucagon A binge eatingdisorder Topical 399 glucagon Hyperglycemia Topical 400 glucagonPostprandial hyperglycemia Topical 401 glucagon Nicotine dependenceTopical 402 glucagon A central nervous system (CNS) Topical disorder 403glucagon Alzheimer's disease or Parkinson's Topical disease 404 NN-9277A disease or condition responsive to Topical treatment with a GLP-1receptor agonist 405 NN-9277 Metabolic or endocrine disorder Topical 406NN-9277 Diabetes Topical 407 NN-9277 Diabetes with Alzheimer's disease,Topical diabetes with dementia, diabetes with Alzheimer's disease anddementia, diabetes with obesity, diabetes with non-alcoholic fatty liverdisease (NAFLD), diabetes with non-alcoholic steatohepatitis (NASH),diabetes with NAFLD and NASH, or diabetes with a cardiovascular disease408 NN-9277 A liver disease or disorder Topical 409 NN-9277 Compensatedliver cirrhosis Topical 410 NN-9277 Non-alcoholic steatohepatitis (NASH)Topical or non-alcoholic fatty liver disease (NAFLD) 411 NN-9277 A bingeeating disorder Topical 412 NN-9277 Hyperglycemia Topical 413 NN-9277Postprandial hyperglycemia Topical 414 NN-9277 Nicotine dependenceTopical 415 NN-9277 A central nervous system (CNS) Topical disorder 416NN-9277 Alzheimer's disease or Parkinson's Topical disease 417 NN-9423 Adisease or condition responsive to Topical treatment with a GLP-1receptor agonist 418 NN-9423 Metabolic or endocrine disorder Topical 419NN-9423 Diabetes Topical 420 NN-9423 Diabetes with Alzheimer's disease,Topical diabetes with dementia, diabetes with Alzheimer's disease anddementia, diabetes with obesity, diabetes with non-alcoholic fatty liverdisease (NAFLD), diabetes with non-alcoholic steatohepatitis (NASH),diabetes with NAFLD and NASH, or diabetes with a cardiovascular disease421 NN-9423 A liver disease or disorder Topical 422 NN-9423 Compensatedliver cirrhosis Topical 423 NN-9423 Non-alcoholic steatohepatitis (NASH)Topical or non-alcoholic fatty liver disease (NAFLD) 424 NN-9423 A bingeeating disorder Topical 425 NN-9423 Hyperglycemia Topical 426 NN-9423Postprandial hyperglycemia Topical 427 NN-9423 Nicotine dependenceTopical 428 NN-9423 A central nervous system (CNS) Topical disorder 429NN-9423 Alzheimer's disease or Parkinson's Topical disease 430 Growthhormone Growth disorder Trans-epithelial 431 Growth hormone Growthhormone deficiency or Trans-epithelial disorder (GHD) 432 Growth hormoneAcquired, congenital, or idiopathic Trans-epithelial GHD; or combinationthereof 433 Growth hormone GHD as a result of trauma, infection,Trans-epithelial radiation therapy, or tumor growth 434 Growth hormoneAdult-onset GHD Trans-epithelial 435 Recombinant growth Growth disorderTrans-epithelial hormone (rHGH) 436 Recombinant growth Growth hormonedeficiency or Trans-epithelial hormone (rHGH) disorder (GHD) 437Recombinant growth Acquired, congenital, or idiopathic Trans-epithelialhormone (rHGH) GHD; or combination thereof 438 Recombinant growth GHD asa result of trauma, infection, Trans-epithelial hormone (rHGH) radiationtherapy, or tumor growth 439 Recombinant growth Adult-onset GHDTrans-epithelial hormone (rHGH) 440 Somatropin Growth disorderTrans-epithelial 441 Somatropin Growth hormone deficiency orTrans-epithelial disorder (GHD) 442 Somatropin Acquired, congenital, oridiopathic Trans-epithelial GHD; or combination thereof 443 SomatropinGHD as a result of trauma, infection, Trans-epithelial radiationtherapy, or tumor growth 444 Somatropin Adult-onset GHD Trans-epithelial445 Somapacitan Growth disorder Trans-epithelial 446 Somapacitan Growthhormone deficiency or Trans-epithelial disorder (GHD) 447 SomapacitanAcquired, congenital, or idiopathic Trans-epithelial GHD; or combinationthereof 448 Somapacitan GHD as a result of trauma, infection,Trans-epithelial radiation therapy, or tumor growth 449 SomapacitanAdult-onset GHD Trans-epithelial 450 Lonapegsomatropin Growth disorderTrans-epithelial 451 Lonapegsomatropin Growth hormone deficiency orTrans-epithelial disorder (GHD) 452 Lonapegsomatropin Acquired,congenital, or idiopathic Trans-epithelial GHD; or combination thereof453 Lonapegsomatropin GHD as a result of trauma, infection,Trans-epithelial radiation therapy, or tumor growth 454Lonapegsomatropin Adult-onset GHD Trans-epithelial 455 YPEG-somatropinGrowth disorder Trans-epithelial 456 YPEG-somatropin Growth hormonedeficiency or Trans-epithelial disorder (GHD) 457 YPEG-somatropinAcquired, congenital, or idiopathic Trans-epithelial GHD; or combinationthereof 458 YPEG-somatropin GHD as a result of trauma, infection,Trans-epithelial radiation therapy, or tumor growth 459 YPEG-somatropinAdult-onset GHD Trans-epithelial 460 Efpegsomatropin Growth disorderTrans-epithelial 461 Efpegsomatropin Growth hormone deficiency orTrans-epithelial disorder (GHD) 462 Efpegsomatropin Acquired,congenital, or idiopathic Trans-epithelial GHD; or combination thereof463 Efpegsomatropin GHD as a result of trauma, infection,Trans-epithelial radiation therapy, or tumor growth 464 EfpegsomatropinAdult-onset GHD Trans-epithelial 465 Somatrogon Growth disorderTrans-epithelial 466 Somatrogon Growth hormone deficiency orTrans-epithelial disorder (GHD) 467 Somatrogon Acquired, congenital, oridiopathic Trans-epithelial GHD; or combination thereof 468 SomatrogonGHD as a result of trauma, infection, Trans-epithelial radiationtherapy, or tumor growth 469 Somatrogon Adult-onset GHD Trans-epithelial470 TJ-101 Growth disorder Trans-epithelial 471 TJ-101 Growth hormonedeficiency or Trans-epithelial disorder (GHD) 472 TJ-101 Acquired,congenital, or idiopathic Trans-epithelial GHD; or combination thereof473 TJ-101 GHD as a result of trauma, infection, Trans-epithelialradiation therapy, or tumor growth 474 TJ-101 Adult-onset GHDTrans-epithelial 475 ALT-P1 Growth disorder Trans-epithelial 476 ALT-P1Growth hormone deficiency or Trans-epithelial disorder (GHD) 477 ALT-P1Acquired, congenital, or idiopathic Trans-epithelial GHD; or combinationthereof 478 ALT-P1 GHD as a result of trauma, infection,Trans-epithelial radiation therapy, or tumor growth 479 ALT-P1Adult-onset GHD Trans-epithelial 480 JR-142 Growth disorderTrans-epithelial 481 JR-142 Growth hormone deficiency orTrans-epithelial disorder (GHD) 482 JR-142 Acquired, congenital, oridiopathic Trans-epithelial GHD; or combination thereof 483 JR-142 GHDas a result of trauma, infection, Trans-epithelial radiation therapy, ortumor growth 484 JR-142 Adult-onset GHD Trans-epithelial 485 Growthhormone Growth disorder Epithelial 486 Growth hormone Growth hormonedeficiency or Epithelial disorder (GHD) 487 Growth hormone Acquired,congenital, or idiopathic Epithelial GHD; or combination thereof 488Growth hormone GHD as a result of trauma, infection, Epithelialradiation therapy, or tumor growth 489 Growth hormone Adult-onset GHDEpithelial 490 Recombinant growth Growth disorder Epithelial hormone(rHGH) 491 Recombinant growth Growth hormone deficiency or Epithelialhormone (rHGH) disorder (GHD) 492 Recombinant growth Acquired,congenital, or idiopathic Epithelial hormone (rHGH) GHD; or combinationthereof 493 Recombinant growth GHD as a result of trauma, infection,Epithelial hormone (rHGH) radiation therapy, or tumor growth 494Recombinant growth Adult-onset GHD Epithelial hormone (rHGH) 495Somatropin Growth disorder Epithelial 496 Somatropin Growth hormonedeficiency or Epithelial disorder (GHD) 497 Somatropin Acquired,congenital, or idiopathic Epithelial GHD; or combination thereof 498Somatropin GHD as a result of trauma, infection, Epithelial radiationtherapy, or tumor growth 499 Somatropin Adult-onset GHD Epithelial 500Somapacitan Growth disorder Epithelial 501 Somapacitan Growth hormonedeficiency or Epithelial disorder (GHD) 502 Somapacitan Acquired,congenital, or idiopathic Epithelial GHD; or combination thereof 503Somapacitan GHD as a result of trauma, infection, Epithelial radiationtherapy, or tumor growth 504 Somapacitan Adult-onset GHD Epithelial 505Lonapegsomatropin Growth disorder Epithelial 506 LonapegsomatropinGrowth hormone deficiency or Epithelial disorder (GHD) 507Lonapegsomatropin Acquired, congenital, or idiopathic Epithelial GHD; orcombination thereof 508 Lonapegsomatropin GHD as a result of trauma,infection, Epithelial radiation therapy, or tumor growth 509Lonapegsomatropin Adult-onset GHD Epithelial 510 YPEG-somatropin Growthdisorder Epithelial 511 YPEG-somatropin Growth hormone deficiency orEpithelial disorder (GHD) 512 YPEG-somatropin Acquired, congenital, oridiopathic Epithelial GHD; or combination thereof 513 YPEG-somatropinGHD as a result of trauma, infection, Epithelial radiation therapy, ortumor growth 514 YPEG-somatropin Adult-onset GHD Epithelial 515Efpegsomatropin Growth disorder Epithelial 516 Efpegsomatropin Growthhormone deficiency or Epithelial disorder (GHD) 517 EfpegsomatropinAcquired, congenital, or idiopathic Epithelial GHD; or combinationthereof 518 Efpegsomatropin GHD as a result of trauma, infection,Epithelial radiation therapy, or tumor growth 519 EfpegsomatropinAdult-onset GHD Epithelial 520 Somatrogon Growth disorder Epithelial 521Somatrogon Growth hormone deficiency or Epithelial disorder (GHD) 522Somatrogon Acquired, congenital, or idiopathic Epithelial GHD; orcombination thereof 523 Somatrogon GHD as a result of trauma, infection,Epithelial radiation therapy, or tumor growth 524 Somatrogon Adult-onsetGHD Epithelial 525 TJ-101 Growth disorder Epithelial 526 TJ-101 Growthhormone deficiency or Epithelial disorder (GHD) 527 TJ-101 Acquired,congenital, or idiopathic Epithelial GHD; or combination thereof 528TJ-101 GHD as a result of trauma, infection, Epithelial radiationtherapy, or tumor growth 529 TJ-101 Adult-onset GHD Epithelial 530ALT-P1 Growth disorder Epithelial 531 ALT-P1 Growth hormone deficiencyor Epithelial disorder (GHD) 532 ALT-P1 Acquired, congenital, oridiopathic Epithelial GHD; or combination thereof 533 ALT-P1 GHD as aresult of trauma, infection, Epithelial radiation therapy, or tumorgrowth 534 ALT-P1 Adult-onset GHD Epithelial 535 JR-142 Growth disorderEpithelial 536 JR-142 Growth hormone deficiency or Epithelial disorder(GHD) 537 JR-142 Acquired, congenital, or idiopathic Epithelial GHD; orcombination thereof 538 JR-142 GHD as a result of trauma, infection,Epithelial radiation therapy, or tumor growth 539 JR-142 Adult-onset GHDEpithelial 540 Growth hormone Growth disorder Topical 541 Growth hormoneGrowth hormone deficiency or Topical disorder (GHD) 542 Growth hormoneAcquired, congenital, or idiopathic Topical GHD; or combination thereof543 Growth hormone GHD as a result of trauma, infection, Topicalradiation therapy, or tumor growth 544 Growth hormone Adult-onset GHDTopical 545 Recombinant growth Growth disorder Topical hormone (rHGH)546 Recombinant growth Growth hormone deficiency or Topical hormone(rHGH) disorder (GHD) 547 Recombinant growth Acquired, congenital, oridiopathic Topical hormone (rHGH) GHD; or combination thereof 548Recombinant growth GHD as a result of trauma, infection, Topical hormone(rHGH) radiation therapy, or tumor growth 549 Recombinant growthAdult-onset GHD Topical hormone (rHGH) 550 Somatropin Growth disorderTopical 551 Somatropin Growth hormone deficiency or Topical disorder(GHD) 552 Somatropin Acquired, congenital, or idiopathic Topical GHD; orcombination thereof 553 Somatropin GHD as a result of trauma, infection,Topical radiation therapy, or tumor growth 554 Somatropin Adult-onsetGHD Topical 555 Somapacitan Growth disorder Topical 556 SomapacitanGrowth hormone deficiency or Topical disorder (GHD) 557 SomapacitanAcquired, congenital, or idiopathic Topical GHD; or combination thereof558 Somapacitan GHD as a result of trauma, infection, Topical radiationtherapy, or tumor growth 559 Somapacitan Adult-onset GHD Topical 560Lonapegsomatropin Growth disorder Topical 561 Lonapegsomatropin Growthhormone deficiency or Topical disorder (GHD) 562 LonapegsomatropinAcquired, congenital, or idiopathic Topical GHD; or combination thereof563 Lonapegsomatropin GHD as a result of trauma, infection, Topicalradiation therapy, or tumor growth 564 Lonapegsomatropin Adult-onset GHDTopical 565 YPEG-somatropin Growth disorder Topical 566 YPEG-somatropinGrowth hormone deficiency or Topical disorder (GHD) 567 YPEG-somatropinAcquired, congenital, or idiopathic Topical GHD; or combination thereof568 YPEG-somatropin GHD as a result of trauma, infection, Topicalradiation therapy, or tumor growth 569 YPEG-somatropin Adult-onset GHDTopical 570 Efpegsomatropin Growth disorder Topical 571 EfpegsomatropinGrowth hormone deficiency or Topical disorder (GHD) 572 EfpegsomatropinAcquired, congenital, or idiopathic Topical GHD; or combination thereof573 Efpegsomatropin GHD as a result of trauma, infection, Topicalradiation therapy, or tumor growth 574 Efpegsomatropin Adult-onset GHDTopical 575 Somatrogon Growth disorder Topical 576 Somatrogon Growthhormone deficiency or Topical disorder (GHD) 577 Somatrogon Acquired,congenital, or idiopathic Topical GHD; or combination thereof 578Somatrogon GHD as a result of trauma, infection, Topical radiationtherapy, or tumor growth 579 Somatrogon Adult-onset GHD Topical 580TJ-101 Growth disorder Topical 581 TJ-101 Growth hormone deficiency orTopical disorder (GHD) 582 TJ-101 Acquired, congenital, or idiopathicTopical GHD; or combination thereof 583 TJ-101 GHD as a result oftrauma, infection, Topical radiation therapy, or tumor growth 584 TJ-101Adult-onset GHD Topical 585 ALT-P1 Growth disorder Topical 586 ALT-P1Growth hormone deficiency or Topical disorder (GHD) 587 ALT-P1 Acquired,congenital, or idiopathic Topical GHD; or combination thereof 588 ALT-P1GHD as a result of trauma, infection, Topical radiation therapy, ortumor growth 589 ALT-P1 Adult-onset GHD Topical 590 JR-142 Growthdisorder Topical 591 JR-142 Growth hormone deficiency or Topicaldisorder (GHD) 592 JR-142 Acquired, congenital, or idiopathic TopicalGHD; or combination thereof 593 JR-142 GHD as a result of trauma,infection, Topical radiation therapy, or tumor growth 594 JR-142Adult-onset GHD Topical 595 TNF-alpha inhibitor A disease or conditionresponsive to Trans-epithelial treatment with a TNF-alpha inhibitor 596TNF-alpha inhibitor Inflammatory disease or disorder Trans-epithelial597 TNF-alpha inhibitor Inflammatory bowel disease Trans-epithelial 598TNF-alpha inhibitor Ulcerative colitis Trans-epithelial 599 TNF-alphainhibitor Crohn's disease Trans-epithelial 600 TNF-alpha inhibitor IlealCrohn's disease Trans-epithelial 601 TNF-alpha inhibitor Ankylosingspondylitis, asthma, Trans-epithelial Behcet's disease, hidradenitissuppurativa, an inflammatory disease, an inflammatory bowel disease,insulin-dependent (type 1) diabetes, type 2 diabetes, juvenilerheumatoid arthritis, Kawasaki disease, lower back pain, osteoarthritis,pouchitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum,rheumatoid arthritis, spondylarthritis, uveitis, or combinations thereof602 Adalimumab A disease or condition responsive to Trans-epithelialtreatment with a TNF-alpha inhibitor 603 Adalimumab Inflammatory diseaseor disorder Trans-epithelial 604 Adalimumab Inflammatory bowel diseaseTrans-epithelial 605 Adalimumab Ulcerative colitis Trans-epithelial 606Adalimumab Crohn's disease Trans-epithelial 607 Adalimumab Ileal Crohn'sdisease Trans-epithelial 608 Adalimumab Ankylosing spondylitis, asthma,Trans-epithelial Behcet's disease, hidradenitis suppurativa, aninflammatory disease, an inflammatory bowel disease, insulin-dependent(type 1) diabetes, type 2 diabetes, juvenile rheumatoid arthritis,Kawasaki disease, lower back pain, osteoarthritis, pouchitis, psoriasis,psoriatic arthritis, pyoderma gangrenosum, rheumatoid arthritis,spondylarthritis, uveitis, or combinations thereof 609 Certolizumabpegol A disease or condition responsive to Trans-epithelial treatmentwith a TNF-alpha inhibitor 610 Certolizumab pegol Inflammatory diseaseor disorder Trans-epithelial 611 Certolizumab pegol Inflammatory boweldisease Trans-epithelial 612 Certolizumab pegol Ulcerative colitisTrans-epithelial 613 Certolizumab pegol Crohn's disease Trans-epithelial614 Certolizumab pegol Ileal Crohn's disease Trans-epithelial 615Certolizumab pegol Ankylosing spondylitis, asthma, Trans-epithelialBehcet's disease, hidradenitis suppurativa, an inflammatory disease, aninflammatory bowel disease, insulin-dependent (type 1) diabetes, type 2diabetes, juvenile rheumatoid arthritis, Kawasaki disease, lower backpain, osteoarthritis, pouchitis, psoriasis, psoriatic arthritis,pyoderma gangrenosum, rheumatoid arthritis, spondylarthritis, uveitis,or combinations thereof 616 Etanercept A disease or condition responsiveto Trans-epithelial treatment with a TNF-alpha inhibitor 617 EtanerceptInflammatory disease or disorder Trans-epithelial 618 EtanerceptInflammatory bowel disease Trans-epithelial 619 Etanercept Ulcerativecolitis Trans-epithelial 620 Etanercept Crohn's disease Trans-epithelial621 Etanercept Ileal Crohn's disease Trans-epithelial 622 EtanerceptAnkylosing spondylitis, asthma, Trans-epithelial Behcet's disease,hidradenitis suppurativa, an inflammatory disease, an inflammatory boweldisease, insulin-dependent (type 1) diabetes, type 2 diabetes, juvenilerheumatoid arthritis, Kawasaki disease, lower back pain, osteoarthritis,pouchitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum,rheumatoid arthritis, spondylarthritis, uveitis, or combinations thereof623 Golimumab A disease or condition responsive to Trans-epithelialtreatment with a TNF-alpha inhibitor 624 Golimumab Inflammatory diseaseor disorder Trans-epithelial 625 Golimumab Inflammatory bowel diseaseTrans-epithelial 626 Golimumab Ulcerative colitis Trans-epithelial 627Golimumab Crohn's disease Trans-epithelial 628 Golimumab Ileal Crohn'sdisease Trans-epithelial 629 Golimumab Ankylosing spondylitis, asthma,Trans-epithelial Behcet's disease, hidradenitis suppurativa, aninflammatory disease, an inflammatory bowel disease, insulin-dependent(type 1) diabetes, type 2 diabetes, juvenile rheumatoid arthritis,Kawasaki disease, lower back pain, osteoarthritis, pouchitis, psoriasis,psoriatic arthritis, pyoderma gangrenosum, rheumatoid arthritis,spondylarthritis, uveitis, or combinations thereof 630 UstekinumabInflammatory disease or disorder Trans-epithelial 631 UstekinumabInflammatory bowel disease Trans-epithelial 632 Vedolizumab Inflammatorydisease or disorder Trans-epithelial 633 Vedolizumab Inflammatory boweldisease Trans-epithelial 634 Natalizumab Inflammatory disease ordisorder Trans-epithelial 635 Natalizumab Inflammatory bowel diseaseTrans-epithelial 636 TNF-alpha inhibitor A disease or conditionresponsive to Epithelial treatment with a TNF-alpha inhibitor 637TNF-alpha inhibitor Inflammatory disease or disorder Epithelial 638TNF-alpha inhibitor Inflammatory bowel disease Epithelial 639 TNF-alphainhibitor Ulcerative colitis Epithelial 640 TNF-alpha inhibitor Crohn'sdisease Epithelial 641 TNF-alpha inhibitor Ileal Crohn's diseaseEpithelial 642 TNF-alpha inhibitor Ankylosing spondylitis, asthma,Epithelial Behcet's disease, hidradenitis suppurativa, an inflammatorydisease, an inflammatory bowel disease, insulin-dependent (type 1)diabetes, type 2 diabetes, juvenile rheumatoid arthritis, Kawasakidisease, lower back pain, osteoarthritis, pouchitis, psoriasis,psoriatic arthritis, pyoderma gangrenosum, rheumatoid arthritis,spondylarthritis, uveitis, or combinations thereof 643 Adalimumab Adisease or condition responsive to Epithelial treatment with a TNF-alphainhibitor 644 Adalimumab Inflammatory disease or disorder Epithelial 645Adalimumab Inflammatory bowel disease Epithelial 646 AdalimumabUlcerative colitis Epithelial 647 Adalimumab Crohn's disease Epithelial648 Adalimumab Ileal Crohn's disease Epithelial 649 AdalimumabAnkylosing spondylitis, asthma, Epithelial Behcet's disease,hidradenitis suppurativa, an inflammatory disease, an inflammatory boweldisease, insulin-dependent (type 1) diabetes, type 2 diabetes, juvenilerheumatoid arthritis, Kawasaki disease, lower back pain, osteoarthritis,pouchitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum,rheumatoid arthritis, spondylarthritis, uveitis, or combinations thereof650 Certolizumab pegol A disease or condition responsive to Epithelialtreatment with a TNF-alpha inhibitor 651 Certolizumab pegol Inflammatorydisease or disorder Epithelial 652 Certolizumab pegol Inflammatory boweldisease Epithelial 653 Certolizumab pegol Ulcerative colitis Epithelial654 Certolizumab pegol Crohn's disease Epithelial 655 Certolizumab pegolIleal Crohn's disease Epithelial 656 Certolizumab pegol Ankylosingspondylitis, asthma, Epithelial Behcet's disease, hidradenitissuppurativa, an inflammatory disease, an inflammatory bowel disease,insulin-dependent (type 1) diabetes, type 2 diabetes, juvenilerheumatoid arthritis, Kawasaki disease, lower back pain, osteoarthritis,pouchitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum,rheumatoid arthritis, spondylarthritis, uveitis, or combinations thereof657 Etanercept A disease or condition responsive to Epithelial treatmentwith a TNF-alpha inhibitor 658 Etanercept Inflammatory disease ordisorder Epithelial 659 Etanercept Inflammatory bowel disease Epithelial660 Etanercept Ulcerative colitis Epithelial 661 Etanercept Crohn'sdisease Epithelial 662 Etanercept Ileal Crohn's disease Epithelial 663Etanercept Ankylosing spondylitis, asthma, Epithelial Behcet's disease,hidradenitis suppurativa, an inflammatory disease, an inflammatory boweldisease, insulin-dependent (type 1) diabetes, type 2 diabetes, juvenilerheumatoid arthritis, Kawasaki disease, lower back pain, osteoarthritis,pouchitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum,rheumatoid arthritis, spondylarthritis, uveitis, or combinations thereof664 Golimumab A disease or condition responsive to Epithelial treatmentwith a TNF-alpha inhibitor 665 Golimumab Inflammatory disease ordisorder Epithelial 666 Golimumab Inflammatory bowel disease Epithelial667 Golimumab Ulcerative colitis Epithelial 668 Golimumab Crohn'sdisease Epithelial 669 Golimumab Ileal Crohn's disease Epithelial 670Golimumab Ankylosing spondylitis, asthma, Epithelial Behcet's disease,hidradenitis suppurativa, an inflammatory disease, an inflammatory boweldisease, insulin-dependent (type 1) diabetes, type 2 diabetes, juvenilerheumatoid arthritis, Kawasaki disease, lower back pain, osteoarthritis,pouchitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum,rheumatoid arthritis, spondylarthritis, uveitis, or combinations thereof671 Ustekinumab Inflammatory disease or disorder Epithelial 672Ustekinumab Inflammatory bowel disease Epithelial 673 VedolizumabInflammatory disease or disorder Epithelial 674 Vedolizumab Inflammatorybowel disease Epithelial 675 Natalizumab Inflammatory disease ordisorder Epithelial 676 Natalizumab Inflammatory bowel diseaseEpithelial 677 TNF-alpha inhibitor A disease or condition responsive toTopical treatment with a TNF-alpha inhibitor 678 TNF-alpha inhibitorInflammatory disease or disorder Topical 679 TNF-alpha inhibitorInflammatory bowel disease Topical 680 TNF-alpha inhibitor Ulcerativecolitis Topical 681 TNF-alpha inhibitor Crohn's disease Topical 682TNF-alpha inhibitor Ileal Crohn's disease Topical 683 TNF-alphainhibitor Ankylosing spondylitis, asthma, Topical Behcet's disease,hidradenitis suppurativa, an inflammatory disease, an inflammatory boweldisease, insulin-dependent (type 1) diabetes, type 2 diabetes, juvenilerheumatoid arthritis, Kawasaki disease, lower back pain, osteoarthritis,pouchitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum,rheumatoid arthritis, spondylarthritis, uveitis, or combinations thereof684 Adalimumab A disease or condition responsive to Topical treatmentwith a TNF-alpha inhibitor 685 Adalimumab Inflammatory disease ordisorder Topical 686 Adalimumab Inflammatory bowel disease Topical 687Adalimumab Ulcerative colitis Topical 688 Adalimumab Crohn's diseaseTopical 689 Adalimumab Ileal Crohn's disease Topical 690 AdalimumabAnkylosing spondylitis, asthma, Topical Behcet's disease, hidradenitissuppurativa, an inflammatory disease, an inflammatory bowel disease,insulin-dependent (type 1) diabetes, type 2 diabetes, juvenilerheumatoid arthritis, Kawasaki disease, lower back pain, osteoarthritis,pouchitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum,rheumatoid arthritis, spondylarthritis, uveitis, or combinations thereof691 Certolizumab pegol A disease or condition responsive to Topicaltreatment with a TNF-alpha inhibitor 692 Certolizumab pegol Inflammatorydisease or disorder Topical 693 Certolizumab pegol Inflammatory boweldisease Topical 694 Certolizumab pegol Ulcerative colitis Topical 695Certolizumab pegol Crohn's disease Topical 696 Certolizumab pegol IlealCrohn's disease Topical 697 Certolizumab pegol Ankylosing spondylitis,asthma, Topical Behcet's disease, hidradenitis suppurativa, aninflammatory disease, an inflammatory bowel disease, insulin-dependent(type 1) diabetes, type 2 diabetes, juvenile rheumatoid arthritis,Kawasaki disease, lower back pain, osteoarthritis, pouchitis, psoriasis,psoriatic arthritis, pyoderma gangrenosum, rheumatoid arthritis,spondylarthritis, uveitis, or combinations thereof 698 Etanercept Adisease or condition responsive to Topical treatment with a TNF-alphainhibitor 699 Etanercept Inflammatory disease or disorder Topical 700Etanercept Inflammatory bowel disease Topical 701 Etanercept Ulcerativecolitis Topical 702 Etanercept Crohn's disease Topical 703 EtanerceptIleal Crohn's disease Topical 704 Etanercept Ankylosing spondylitis,asthma, Topical Behcet's disease, hidradenitis suppurativa, aninflammatory disease, an inflammatory bowel disease, insulin-dependent(type 1) diabetes, type 2 diabetes, juvenile rheumatoid arthritis,Kawasaki disease, lower back pain, osteoarthritis, pouchitis, psoriasis,psoriatic arthritis, pyoderma gangrenosum, rheumatoid arthritis,spondylarthritis, uveitis, or combinations thereof 705 Golimumab Adisease or condition responsive to Topical treatment with a TNF-alphainhibitor 706 Golimumab Inflammatory disease or disorder Topical 707Golimumab Inflammatory bowel disease Topical 708 Golimumab Ulcerativecolitis Topical 709 Golimumab Crohn's disease Topical 710 GolimumabIleal Crohn's disease Topical 711 Golimumab Ankylosing spondylitis,asthma, Topical Behcet's disease, hidradenitis suppurativa, aninflammatory disease, an inflammatory bowel disease, insulin-dependent(type 1) diabetes, type 2 diabetes, juvenile rheumatoid arthritis,Kawasaki disease, lower back pain, osteoarthritis, pouchitis, psoriasis,psoriatic arthritis, pyoderma gangrenosum, rheumatoid arthritis,spondylarthritis, uveitis, or combinations thereof 712 UstekinumabInflammatory disease or disorder Topical 713 Ustekinumab Inflammatorybowel disease Topical 714 Vedolizumab Inflammatory disease or disorderTopical 715 Vedolizumab Inflammatory bowel disease Topical 716Natalizumab Inflammatory disease or disorder Topical 717 NatalizumabInflammatory bowel disease Topical 718 An alternative HemophiliaTrans-epithelial coagulation promotor (ACP) 719 An alternativeHemophilia A Trans-epithelial coagulation promotor (ACP) 720 Analternative Hemophilia B Trans-epithelial coagulation promotor (ACP) 721An alternative Von Willebrand disease Trans-epithelial coagulationpromotor (ACP) 722 An anti-tissue factor Hemophilia Trans-epithelialpathway inhibitor (anti-TFPI) 723 An anti-tissue factor Hemophilia ATrans-epithelial pathway inhibitor (anti-TFPI) 724 An anti-tissue factorHemophilia B Trans-epithelial pathway inhibitor (anti-TFPI) 725 Ananti-tissue factor Von Willebrand disease Trans-epithelial pathwayinhibitor (anti-TFPI) 726 Concizumab Hemophilia Trans-epithelial 727Concizumab Hemophilia A Trans-epithelial 728 Concizumab Hemophilia BTrans-epithelial 729 Concizumab Von Willebrand disease Trans-epithelial730 Factor VII mimetic Hemophilia Trans-epithelial 731 Factor VIImimetic Hemophilia A Trans-epithelial 732 Factor VII mimetic HemophiliaB Trans-epithelial 733 Factor VII mimetic Von Willebrand diseaseTrans-epithelial 734 Emicizumab Hemophilia Trans-epithelial 735Emicizumab Hemophilia A Trans-epithelial 736 Emicizumab Hemophilia BTrans-epithelial 737 Emicizumab Von Willebrand disease Trans-epithelial738 An alternative Hemophilia Epithelial coagulation promotor (ACP) 739An alternative Hemophilia A Epithelial coagulation promotor (ACP) 740 Analternative Hemophilia B Epithelial coagulation promotor (ACP) 741 Analternative Von Willebrand disease Epithelial coagulation promotor (ACP)742 An anti-tissue factor Hemophilia Epithelial pathway inhibitor(anti-TFPI) 743 An anti-tissue factor Hemophilia A Epithelial pathwayinhibitor (anti-TFPI) 744 An anti-tissue factor Hemophilia B Epithelialpathway inhibitor (anti-TFPI) 745 An anti-tissue factor Von Willebranddisease Epithelial pathway inhibitor (anti-TFPI) 746 ConcizumabHemophilia Epithelial 747 Concizumab Hemophilia A Epithelial 748Concizumab Hemophilia B Epithelial 749 Concizumab Von Willebrand diseaseEpithelial 750 Factor VII mimetic Hemophilia Epithelial 751 Factor VIImimetic Hemophilia A Epithelial 752 Factor VII mimetic Hemophilia BEpithelial 753 Factor VII mimetic Von Willebrand disease Epithelial 754Emicizumab Hemophilia Epithelial 755 Emicizumab Hemophilia A Epithelial756 Emicizumab Hemophilia B Epithelial 757 Emicizumab Von Willebranddisease Epithelial 758 An alternative Hemophilia Topical coagulationpromotor (ACP) 759 An alternative Hemophilia A Topical coagulationpromotor (ACP) 760 An alternative Hemophilia B Topical coagulationpromotor (ACP) 761 An alternative Von Willebrand disease Topicalcoagulation promotor (ACP) 762 An anti-tissue factor Hemophilia Topicalpathway inhibitor (anti-TFPI) 763 An anti-tissue factor Hemophilia ATopical pathway inhibitor (anti-TFPI) 764 An anti-tissue factorHemophilia B Topical pathway inhibitor (anti-TFPI) 765 An anti-tissuefactor Von Willebrand disease Topical pathway inhibitor (anti-TFPI) 766Concizumab Hemophilia Topical 767 Concizumab Hemophilia A Topical 768Concizumab Hemophilia B Topical 769 Concizumab Von Willebrand diseaseTopical 770 Factor VII mimetic Hemophilia Topical 771 Factor VII mimeticHemophilia A Topical 772 Factor VII mimetic Hemophilia B Topical 773Factor VII mimetic Von Willebrand disease Topical 774 EmicizumabHemophilia Topical 775 Emicizumab Hemophilia A Topical 776 EmicizumabHemophilia B Topical 777 Emicizumab Von Willebrand disease Topical 778Abatacept Autoimmune disease or condition Trans-epithelial 779 AbataceptRheumatoid arthritis Trans-epithelial 780 Abatacept FibrosisTrans-epithelial 781 Teriparatide Autoimmune disease or conditionTrans-epithelial 782 Teriparatide Rheumatoid arthritis Trans-epithelial783 Teriparatide Fibrosis Trans-epithelial 784 Pegfilgrastim Autoimmunedisease or condition Trans-epithelial 785 Pegfilgrastim Rheumatoidarthritis Trans-epithelial 786 Pegfilgrastim Fibrosis Trans-epithelial787 Sargramostim Autoimmune disease or condition Trans-epithelial 788Sargramostim Rheumatoid arthritis Trans-epithelial 789 SargramostimFibrosis Trans-epithelial 790 Tocilizumab Autoimmune disease orcondition Trans-epithelial 791 Tocilizumab Rheumatoid arthritisTrans-epithelial 792 Tocilizumab Fibrosis Trans-epithelial 793Interferon beta-1a Autoimmune disease or condition Trans-epithelial 794Interferon beta-1a Rheumatoid arthritis Trans-epithelial 795 Interferonbeta-1a Fibrosis Trans-epithelial 796 Abatacept Autoimmune disease orcondition Epithelial 797 Abatacept Rheumatoid arthritis Epithelial 798Abatacept Fibrosis Epithelial 799 Teriparatide Autoimmune disease orcondition Epithelial 800 Teriparatide Rheumatoid arthritis Epithelial801 Teriparatide Fibrosis Epithelial 802 Pegfilgrastim Autoimmunedisease or condition Epithelial 803 Pegfilgrastim Rheumatoid arthritisEpithelial 804 Pegfilgrastim Fibrosis Epithelial 805 SargramostimAutoimmune disease or condition Epithelial 806 Sargramostim Rheumatoidarthritis Epithelial 807 Sargramostim Fibrosis Epithelial 808Tocilizumab Autoimmune disease or condition Epithelial 809 TocilizumabRheumatoid arthritis Epithelial 810 Tocilizumab Fibrosis Epithelial 811Interferon beta-1a Autoimmune disease or condition Epithelial 812Interferon beta-1a Rheumatoid arthritis Epithelial 813 Interferonbeta-1a Fibrosis Epithelial 814 Abatacept Autoimmune disease orcondition Topical 815 Abatacept Rheumatoid arthritis Topical 816Abatacept Fibrosis Topical 817 Teriparatide Autoimmune disease orcondition Topical 818 Teriparatide Rheumatoid arthritis Topical 819Teriparatide Fibrosis Topical 820 Pegfilgrastim Autoimmune disease orcondition Topical 821 Pegfilgrastim Rheumatoid arthritis Topical 822Pegfilgrastim Fibrosis Topical 823 Sargramostim Autoimmune disease orcondition Topical 824 Sargramostim Rheumatoid arthritis Topical 825Sargramostim Fibrosis Topical 826 Tocilizumab Autoimmune disease orcondition Topical 827 Tocilizumab Rheumatoid arthritis Topical 828Tocilizumab Fibrosis Topical 829 Interferon beta-1a Autoimmune diseaseor condition Topical 830 Interferon beta-1a Rheumatoid arthritis Topical831 Interferon beta-1a Fibrosis Topical 832 Natalizumab Autoimmunedisease or condition Trans-epithelial 833 Vedolizumab Autoimmune diseaseor condition Trans-epithelial 834 Ustekinumab Autoimmune disease orcondition Trans-epithelial 835 Denosumab Autoimmune disease or conditionTrans-epithelial 836 Secukinumab Metabolic or endocrine disorderTrans-epithelial 837 Natalizumab Autoimmune disease or conditionEpithelial 838 Vedolizumab Autoimmune disease or condition Epithelial839 Ustekinumab Autoimmune disease or condition Epithelial 840 DenosumabAutoimmune disease or condition Epithelial 841 Secukinumab Metabolic orendocrine disorder Epithelial 842 Natalizumab Autoimmune disease orcondition Topical 843 Vedolizumab Autoimmune disease or conditionTopical 844 Ustekinumab Autoimmune disease or condition Topical 845Denosumab Autoimmune disease or condition Topical 846 SecukinumabMetabolic or endocrine disorder Topical 847 Insulin Metabolic orendocrine disease or Trans-epithelial condition 848 Insulin DiabetesTrans-epithelial 849 Insulin Obesity Trans-epithelial 850 InsulinHypercholesterolemia Trans-epithelial 851 Insulin A lipid metabolismdisorder Trans-epithelial 852 Insulin Hyperlipidemia Trans-epithelial853 Insulin Atherosclerosis Trans-epithelial 854 TNF-alpha inhibitorMetabolic or endocrine disease or Trans-epithelial condition 855TNF-alpha inhibitor Diabetes Trans-epithelial 856 TNF-alpha inhibitorObesity Trans-epithelial 857 TNF-alpha inhibitor HypercholesterolemiaTrans-epithelial 858 TNF-alpha inhibitor A lipid metabolism disorderTrans-epithelial 859 TNF-alpha inhibitor Hyperlipidemia Trans-epithelial860 TNF-alpha inhibitor Atherosclerosis Trans-epithelial 861 AdalimumabMetabolic or endocrine disease or Trans-epithelial condition 862Adalimumab Diabetes Trans-epithelial 863 Adalimumab ObesityTrans-epithelial 864 Adalimumab Hypercholesterolemia Trans-epithelial865 Adalimumab A lipid metabolism disorder Trans-epithelial 866Adalimumab Hyperlipidemia Trans-epithelial 867 AdalimumabAtherosclerosis Trans-epithelial 868 A proprotein Metabolic or endocrinedisease or Trans-epithelial convertase PC9 condition (PCSK9) inhibitor869 A proprotein Diabetes Trans-epithelial convertase PC9 (PCSK9)inhibitor 870 A proprotein Obesity Trans-epithelial convertase PC9(PCSK9) inhibitor 871 A proprotein Hypercholesterolemia Trans-epithelialconvertase PC9 (PCSK9) inhibitor 872 A proprotein A lipid metabolismdisorder Trans-epithelial convertase PC9 (PCSK9) inhibitor 873 Aproprotein Hyperlipidemia Trans-epithelial convertase PC9 (PCSK9)inhibitor 874 A proprotein Atherosclerosis Trans-epithelial convertasePC9 (PCSK9) inhibitor 875 Alirocumab Metabolic or endocrine disease orTrans-epithelial condition 876 Alirocumab Diabetes Trans-epithelial 877Alirocumab Obesity Trans-epithelial 878 Alirocumab HypercholesterolemiaTrans-epithelial 879 Alirocumab A lipid metabolism disorderTrans-epithelial 880 Alirocumab Hyperlipidemia Trans-epithelial 881Alirocumab Atherosclerosis Trans-epithelial 882 Evolocumab Metabolic orendocrine disease or Trans-epithelial condition 883 Evolocumab DiabetesTrans-epithelial 884 Evolocumab Obesity Trans-epithelial 885 EvolocumabHypercholesterolemia Trans-epithelial 886 Evolocumab A lipid metabolismdisorder Trans-epithelial 887 Evolocumab Hyperlipidemia Trans-epithelial888 Evolocumab Atherosclerosis Trans-epithelial 889 Peptide YY ligandMetabolic or endocrine disease or Trans-epithelial condition 890 PeptideYY ligand Diabetes Trans-epithelial 891 Peptide YY ligand ObesityTrans-epithelial 892 Peptide YY ligand HypercholesterolemiaTrans-epithelial 893 Peptide YY ligand A lipid metabolism disorderTrans-epithelial 894 Peptide YY ligand Hyperlipidemia Trans-epithelial895 Peptide YY ligand Atherosclerosis Trans-epithelial 896 NN-9747Metabolic or endocrine disease or Trans-epithelial condition 897 NN-9747Diabetes Trans-epithelial 898 NN-9747 Obesity Trans-epithelial 899NN-9747 Hypercholesterolemia Trans-epithelial 900 NN-9747 A lipidmetabolism disorder Trans-epithelial 901 NN-9747 HyperlipidemiaTrans-epithelial 902 NN-9747 Atherosclerosis Trans-epithelial 903NN-9748 Metabolic or endocrine disease or Trans-epithelial condition 904NN-9748 Diabetes Trans-epithelial 905 NN-9748 Obesity Trans-epithelial906 NN-9748 Hypercholesterolemia Trans-epithelial 907 NN-9748 A lipidmetabolism disorder Trans-epithelial 908 NN-9748 HyperlipidemiaTrans-epithelial 909 NN-9748 Atherosclerosis Trans-epithelial 910NN-9775 Metabolic or endocrine disease or Trans-epithelial condition 911NN-9775 Diabetes Trans-epithelial 912 NN-9775 Obesity Trans-epithelial913 NN-9775 Hypercholesterolemia Trans-epithelial 914 NN-9775 A lipidmetabolism disorder Trans-epithelial 915 NN-9775 HyperlipidemiaTrans-epithelial 916 NN-9775 Atherosclerosis Trans-epithelial 917FSI-965 Metabolic or endocrine disease or Trans-epithelial condition 918FSI-965 Diabetes Trans-epithelial 919 FSI-965 Obesity Trans-epithelial920 FSI-965 Hypercholesterolemia Trans-epithelial 921 FSI-965 A lipidmetabolism disorder Trans-epithelial 922 FSI-965 HyperlipidemiaTrans-epithelial 923 FSI-965 Atherosclerosis Trans-epithelial 924NN-0385-0434 Metabolic or endocrine disease or Trans-epithelialcondition 925 NN-0385-0434 Diabetes Trans-epithelial 926 NN-0385-0434Obesity Trans-epithelial 927 NN-0385-0434 HypercholesterolemiaTrans-epithelial 928 NN-0385-0434 A lipid metabolism disorderTrans-epithelial 929 NN-0385-0434 Hyperlipidemia Trans-epithelial 930NN-0385-0434 Atherosclerosis Trans-epithelial 931 Amylin analogMetabolic or endocrine disease or Trans-epithelial condition 932 Amylinanalog Diabetes Trans-epithelial 933 Amylin analog ObesityTrans-epithelial 934 Amylin analog Hypercholesterolemia Trans-epithelial935 Amylin analog A lipid metabolism disorder Trans-epithelial 936Amylin analog Hyperlipidemia Trans-epithelial 937 Amylin analogAtherosclerosis Trans-epithelial 938 AM-833 Metabolic or endocrinedisease or Trans-epithelial condition 939 AM-833 DiabetesTrans-epithelial 940 AM-833 Obesity Trans-epithelial 941 AM-833Hypercholesterolemia Trans-epithelial 942 AM-833 A lipid metabolismdisorder Trans-epithelial 943 AM-833 Hyperlipidemia Trans-epithelial 944AM-833 Atherosclerosis Trans-epithelial 945 Insulin Metabolic orendocrine disease or Epithelial condition 946 Insulin DiabetesEpithelial 947 Insulin Obesity Epithelial 948 InsulinHypercholesterolemia Epithelial 949 Insulin A lipid metabolism disorderEpithelial 950 Insulin Hyperlipidemia Epithelial 951 InsulinAtherosclerosis Epithelial 952 TNF-alpha inhibitor Metabolic orendocrine disease or Epithelial condition 953 TNF-alpha inhibitorDiabetes Epithelial 954 TNF-alpha inhibitor Obesity Epithelial 955TNF-alpha inhibitor Hypercholesterolemia Epithelial 956 TNF-alphainhibitor A lipid metabolism disorder Epithelial 957 TNF-alpha inhibitorHyperlipidemia Epithelial 958 TNF-alpha inhibitor AtherosclerosisEpithelial 959 Adalimumab Metabolic or endocrine disease or Epithelialcondition 960 Adalimumab Diabetes Epithelial 961 Adalimumab ObesityEpithelial 962 Adalimumab Hypercholesterolemia Epithelial 963 AdalimumabA lipid metabolism disorder Epithelial 964 Adalimumab HyperlipidemiaEpithelial 965 Adalimumab Atherosclerosis Epithelial 966 A proproteinMetabolic or endocrine disease or Epithelial convertase PC9 condition(PCSK9) inhibitor 967 A proprotein Diabetes Epithelial convertase PC9(PCSK9) inhibitor 968 A proprotein Obesity Epithelial convertase PC9(PCSK9) inhibitor 969 A proprotein Hypercholesterolemia Epithelialconvertase PC9 (PCSK9) inhibitor 970 A proprotein A lipid metabolismdisorder Epithelial convertase PC9 (PCSK9) inhibitor 971 A proproteinHyperlipidemia Epithelial convertase PC9 (PCSK9) inhibitor 972 Aproprotein Atherosclerosis Epithelial convertase PC9 (PCSK9) inhibitor973 Alirocumab Metabolic or endocrine disease or Epithelial condition974 Alirocumab Diabetes Epithelial 975 Alirocumab Obesity Epithelial 976Alirocumab Hypercholesterolemia Epithelial 977 Alirocumab A lipidmetabolism disorder Epithelial 978 Alirocumab Hyperlipidemia Epithelial979 Alirocumab Atherosclerosis Epithelial 980 Evolocumab Metabolic orendocrine disease or Epithelial condition 981 Evolocumab DiabetesEpithelial 982 Evolocumab Obesity Epithelial 983 EvolocumabHypercholesterolemia Epithelial 984 Evolocumab A lipid metabolismdisorder Epithelial 985 Evolocumab Hyperlipidemia Epithelial 986Evolocumab Atherosclerosis Epithelial 987 Peptide YY ligand Metabolic orendocrine disease or Epithelial condition 988 Peptide YY ligand DiabetesEpithelial 989 Peptide YY ligand Obesity Epithelial 990 Peptide YYligand Hypercholesterolemia Epithelial 991 Peptide YY ligand A lipidmetabolism disorder Epithelial 992 Peptide YY ligand HyperlipidemiaEpithelial 993 Peptide YY ligand Atherosclerosis Epithelial 994 NN-9747Metabolic or endocrine disease or Epithelial condition 995 NN-9747Diabetes Epithelial 996 NN-9747 Obesity Epithelial 997 NN-9747Hypercholesterolemia Epithelial 998 NN-9747 A lipid metabolism disorderEpithelial 999 NN-9747 Hyperlipidemia Epithelial 1000 NN-9747Atherosclerosis Epithelial 1001 NN-9748 Metabolic or endocrine diseaseor Epithelial condition 1002 NN-9748 Diabetes Epithelial 1003 NN-9748Obesity Epithelial 1004 NN-9748 Hypercholesterolemia Epithelial 1005NN-9748 A lipid metabolism disorder Epithelial 1006 NN-9748Hyperlipidemia Epithelial 1007 NN-9748 Atherosclerosis Epithelial 1008NN-9775 Metabolic or endocrine disease or Epithelial condition 1009NN-9775 Diabetes Epithelial 1010 NN-9775 Obesity Epithelial 1011 NN-9775Hypercholesterolemia Epithelial 1012 NN-9775 A lipid metabolism disorderEpithelial 1013 NN-9775 Hyperlipidemia Epithelial 1014 NN-9775Atherosclerosis Epithelial 1015 FSI-965 Metabolic or endocrine diseaseor Epithelial condition 1016 FSI-965 Diabetes Epithelial 1017 FSI-965Obesity Epithelial 1018 FSI-965 Hypercholesterolemia Epithelial 1019FSI-965 A lipid metabolism disorder Epithelial 1020 FSI-965Hyperlipidemia Epithelial 1021 FSI-965 Atherosclerosis Epithelial 1022NN-0385-0434 Metabolic or endocrine disease or Epithelial condition 1023NN-0385-0434 Diabetes Epithelial 1024 NN-0385-0434 Obesity Epithelial1025 NN-0385-0434 Hypercholesterolemia Epithelial 1026 NN-0385-0434 Alipid metabolism disorder Epithelial 1027 NN-0385-0434 HyperlipidemiaEpithelial 1028 NN-0385-0434 Atherosclerosis Epithelial 1029 Amylinanalog Metabolic or endocrine disease or Epithelial condition 1030Amylin analog Diabetes Epithelial 1031 Amylin analog Obesity Epithelial1032 Amylin analog Hypercholesterolemia Epithelial 1033 Amylin analog Alipid metabolism disorder Epithelial 1034 Amylin analog HyperlipidemiaEpithelial 1035 Amylin analog Atherosclerosis Epithelial 1036 AM-833Metabolic or endocrine disease or Epithelial condition 1037 AM-833Diabetes Epithelial 1038 AM-833 Obesity Epithelial 1039 AM-833Hypercholesterolemia Epithelial 1040 AM-833 A lipid metabolism disorderEpithelial 1041 AM-833 Hyperlipidemia Epithelial 1042 AM-833Atherosclerosis Epithelial 1043 Insulin Metabolic or endocrine diseaseor Topical condition 1044 Insulin Diabetes Topical 1045 Insulin ObesityTopical 1046 Insulin Hypercholesterolemia Topical 1047 Insulin A lipidmetabolism disorder Topical 1048 Insulin Hyperlipidemia Topical 1049Insulin Atherosclerosis Topical 1050 TNF-alpha inhibitor Metabolic orendocrine disease or Topical condition 1051 TNF-alpha inhibitor DiabetesTopical 1052 TNF-alpha inhibitor Obesity Topical 1053 TNF-alphainhibitor Hypercholesterolemia Topical 1054 TNF-alpha inhibitor A lipidmetabolism disorder Topical 1055 TNF-alpha inhibitor HyperlipidemiaTopical 1056 TNF-alpha inhibitor Atherosclerosis Topical 1057 AdalimumabMetabolic or endocrine disease or Topical condition 1058 AdalimumabDiabetes Topical 1059 Adalimumab Obesity Topical 1060 AdalimumabHypercholesterolemia Topical 1061 Adalimumab A lipid metabolism disorderTopical 1062 Adalimumab Hyperlipidemia Topical 1063 AdalimumabAtherosclerosis Topical 1064 A proprotein Metabolic or endocrine diseaseor Topical convertase PC9 condition (PCSK9) inhibitor 1065 A proproteinDiabetes Topical convertase PC9 (PCSK9) inhibitor 1066 A proproteinObesity Topical convertase PC9 (PCSK9) inhibitor 1067 A proproteinHypercholesterolemia Topical convertase PC9 (PCSK9) inhibitor 1068 Aproprotein A lipid metabolism disorder Topical convertase PC9 (PCSK9)inhibitor 1069 A proprotein Hyperlipidemia Topical convertase PC9(PCSK9) inhibitor 1070 A proprotein Atherosclerosis Topical convertasePC9 (PCSK9) inhibitor 1071 Alirocumab Metabolic or endocrine disease orTopical condition 1072 Alirocumab Diabetes Topical 1073 AlirocumabObesity Topical 1074 Alirocumab Hypercholesterolemia Topical 1075Alirocumab A lipid metabolism disorder Topical 1076 AlirocumabHyperlipidemia Topical 1077 Alirocumab Atherosclerosis Topical 1078Evolocumab Metabolic or endocrine disease or Topical condition 1079Evolocumab Diabetes Topical 1080 Evolocumab Obesity Topical 1081Evolocumab Hypercholesterolemia Topical 1082 Evolocumab A lipidmetabolism disorder Topical 1083 Evolocumab Hyperlipidemia Topical 1084Evolocumab Atherosclerosis Topical 1085 Peptide YY ligand Metabolic orendocrine disease or Topical condition 1086 Peptide YY ligand DiabetesTopical 1087 Peptide YY ligand Obesity Topical 1088 Peptide YY ligandHypercholesterolemia Topical 1089 Peptide YY ligand A lipid metabolismdisorder Topical 1090 Peptide YY ligand Hyperlipidemia Topical 1091Peptide YY ligand Atherosclerosis Topical 1092 NN-9747 Metabolic orendocrine disease or Topical condition 1093 NN-9747 Diabetes Topical1094 NN-9747 Obesity Topical 1095 NN-9747 Hypercholesterolemia Topical1096 NN-9747 A lipid metabolism disorder Topical 1097 NN-9747Hyperlipidemia Topical 1098 NN-9747 Atherosclerosis Topical 1099 NN-9748Metabolic or endocrine disease or Topical condition 1100 NN-9748Diabetes Topical 1101 NN-9748 Obesity Topical 1102 NN-9748Hypercholesterolemia Topical 1103 NN-9748 A lipid metabolism disorderTopical 1104 NN-9748 Hyperlipidemia Topical 1105 NN-9748 AtherosclerosisTopical 1106 NN-9775 Metabolic or endocrine disease or Topical condition1107 NN-9775 Diabetes Topical 1108 NN-9775 Obesity Topical 1109 NN-9775Hypercholesterolemia Topical 1110 NN-9775 A lipid metabolism disorderTopical 1111 NN-9775 Hyperlipidemia Topical 1112 NN-9775 AtherosclerosisTopical 1113 FSI-965 Metabolic or endocrine disease or Topical condition1114 FSI-965 Diabetes Topical 1115 FSI-965 Obesity Topical 1116 FSI-965Hypercholesterolemia Topical 1117 FSI-965 A lipid metabolism disorderTopical 1118 FSI-965 Hyperlipidemia Topical 1119 FSI-965 AtherosclerosisTopical 1120 NN-0385-0434 Metabolic or endocrine disease or Topicalcondition 1121 NN-0385-0434 Diabetes Topical 1122 NN-0385-0434 ObesityTopical 1123 NN-0385-0434 Hypercholesterolemia Topical 1124 NN-0385-0434A lipid metabolism disorder Topical 1125 NN-0385-0434 HyperlipidemiaTopical 1126 NN-0385-0434 Atherosclerosis Topical 1127 Amylin analogMetabolic or endocrine disease or Topical condition 1128 Amylin analogDiabetes Topical 1129 Amylin analog Obesity Topical 1130 Amylin analogHypercholesterolemia Topical 1131 Amylin analog A lipid metabolismdisorder Topical 1132 Amylin analog Hyperlipidemia Topical 1133 Amylinanalog Atherosclerosis Topical 1134 AM-833 Metabolic or endocrinedisease or Topical condition 1135 AM-833 Diabetes Topical 1136 AM-833Obesity Topical 1137 AM-833 Hypercholesterolemia Topical 1138 AM-833 Alipid metabolism disorder Topical 1139 AM-833 Hyperlipidemia Topical1140 AM-833 Atherosclerosis Topical

The ingestible device disclosed herein can be used to implement any ofmedical approaches 1-1140.

The ingestible device of the invention can be configured to deliver thedispensable substance comprising the therapeutic agent via the deliverymode of any of the medical approaches 1-1140 according to particularparameters, which can be defined by particular ‘configurations’. In eachconfiguration, the delivery device comprises a housing configured tocontain a dispensable substance comprising a therapeutic agent; and anopening in the housing configured to fluidly connect the dispensablesubstance to an environment outside the housing via the opening.

In configuration 1, the device is configured to deliver the dispensablesubstance to tissue of the GI tract of a subject as a jet viatrans-epithelial delivery.

In some aspects, the device configured for trans-epithelial deliverydelivers the dispensable substance to the GI tract of the subject as ajet with a peak jet power of from about one Watt to about three Watts.The peak jet power may be from about 1.3 Watts to about 2.8 Watts; orfrom about 1.5 Watts to about 2.5 Watts. The peak jet power may be about2.3 Watts.

In some aspects, the device configured for trans-epithelial deliveryprovides an internal pressure of from about 225 psig to about 400 psig.The internal pressure may be from about 250 psig to about 375 psig; orfrom about 300 psig to about 340 psig.

In some aspects, the device configured for trans-epithelial deliverycontains the dispensable substance at a peak fluid pressure of about 200psig to about 375 psig. The dispensable substance may be contained at apeak fluid pressure of from about 220 psig to about 350 psig; at a peakfluid pressure of from about 225 psig to about 375 psig; at a peak fluidpressure of from about 225 psig to about 350 psig; at a peak fluidpressure of from about 225 psig to about 325 psig; or at a peak fluidpressure of from about 280 psig to about 320 psig.

In some aspects, the device configured for trans-epithelial deliverydelivers the dispensable substance as a jet at a peak jet velocity offrom about 25 meters per second to about 45 meters per second. The peakjet velocity may be from about 30 meters per second to about 42 metersper second; or about 34 meters per second to about 39 meters per second.

In some aspects, the device configured for trans-epithelial deliverydelivers the dispensable substance as a jet at a mean jet velocity offrom about 20 meters per second to about 30 meters per second. The meanjet velocity may be from about 25 meters per second to about 30 metersper second.

In some aspects, the device configured for trans-epithelial deliverydelivers the dispensable substance as a jet having jet stable length ofat least about 0.5 millimeter. The jet may have a jet stable length offrom 0.5 millimeter to 20 millimeters; or from about 2 millimeters to 20millimeters; or from about 5 millimeters to 20 millimeters.

In some aspects, the device configured for trans-epithelial deliverydelivers the dispensable substance to tissue of the GI tract of asubject as a jet at a peak jet pressure of from about 100 psig to about250 psig. The peak jet pressure may be from about 140 psig to about 225psig; or from about 180 psig to about 205 psig.

In some aspects, the device configured for trans-epithelial deliverydelivers the dispensable substance to tissue of the GI tract of asubject as a jet at a peak jet force of from about 0.09 N to about 0.15N. The peak jet force may be from about 0.1 N to about 0.14 N; or fromabout 0.11 N to about 0.14 N.

In some aspects, the device configured for trans-epithelial deliverydelivers the dispensable substance to tissue of the GI tract of asubject as a jet having a diameter of from about 0.1 mm to about 2 mm.The jet diameter may be from about 0.1 mm to about 1 mm; from about 0.2mm to about 0.8 mm; from about 0.3 mm to about 0.5 mm; from about 0.3 mmto about 0.4 mm; or about 0.35 mm.

In some aspects, the device configured for trans-epithelial deliveryreleases a dispensable substance volume of from about 50 microliters toabout 800 microliters, about 50 microliters to about 500 microliters,from about 100 microliters to about 450 microliters, from about 200microliters to about 400 microliters, from 250 microliters to about 400microliters, or from about 300 microliters to about 400 microliters.

In some aspects, the device configured for trans-epithelial delivery tothe GI tract of a subject contains a dispensable substance having aviscosity of from about 0.8 cP to about 10 cP.

It is to be understood that each and any of the foregoing aspects ofconfiguration 1 are freely combinable to deliver the dispensablesubstance as a jet to tissue of the GI tract of a subject viatrans-epithelial delivery.

It is to be understood that reference to a jet refers to at least onejet, for example, one, two, three, four, five, six, seven, eight or morejets, optionally two jets, three jets or four jets, and that each jetparameter (e.g., jet power, jet velocity, jet stable length, jetpressure, jet force) refers to each said jet, unless expressly indicatedotherwise.

In configuration 2, the device is configured to deliver the dispensablesubstance to tissue of the GI tract of a subject optionally as a jet viaepithelial delivery.

In some aspects, the device configured for epithelial delivery deliversthe dispensable substance to the GI tract of the subject as a jet with apeak jet power of from about 1 mW to about 4 mW. The peak jet power ofthe jet may be from about 1 mW to about 3.5 mW, or from about 2 mW toabout 3 mW.

In some aspects, the device configured for epithelial delivery providesan internal pressure of from about 3.62 psig to about 21.76 psig. Theinternal pressure may be from about 3.62 psig to about 18.13 psig, fromabout 3.62 psig to about 14.50 psig, from about 3.62 psig to about 10.88psig, from about 3.62 psig to about 7.25 psig, from about 4.35 psig toabout 7.25 psig, or about 4.35 psig.

In some aspects, the device configured for epithelial delivery containsthe dispensable substance at a peak fluid pressure of from about 3.62psig to about 21.76 psig. The peak fluid pressure may be from about 3.62psig to about 18.13 psig, from about 3.62 psig to about 14.50 psig, fromabout 3.62 psig to about 10.88 psig, from about 3.62 psig to about 7.25psig, from about 4.35 psig to about 7.25 psig, or about 4.35 psig.

In some aspects, the device configured for epithelial delivery deliversthe dispensable substance as a jet at a peak jet velocity of 2 m/s toabout 20 m/s. The peak jet velocity of the jet may be from about 3 m/sto about 15 m/s, from about 4 m/s to about 10 m/s, or from about 5 m/sto about 8 m/s.

In some aspects, the device configured for epithelial delivery deliversthe dispensable substance to tissue of the GI tract of a subject as ajet at a peak jet pressure of from about 2 psig to about 10 psig. Thepeak jet pressure of the jet may be from about 2.5 psig to about 8 psig,from about 3 psig to about 6 psig, from about 3.5 psig to about 5 psig,or from about 4 psig to about 5 psig.

In some aspects, the device configured for epithelial delivery deliversthe dispensable substance to tissue of the GI tract of a subject as ajet at a peak jet force of from about 0.5 mN to about 2 mN. The peak jetforce of the jet may be from about 0.6 mN to about 1.8 mN, from about0.7 mN to about 1.6 mN, from about 0.8 mN to about 1.4 mN, from about0.9 mN to about 1.2 mN.

In some aspects, the device configured for epithelial delivery releasesa dispensable substance volume of from about 50 microliters to about 800microliters, about 100 microliters to about 600 microliters, or fromabout 200 microliters to about 400 microliters.

In some aspects, the device configured for epithelial delivery has from25 to 50 nozzles. The device may have from from 30 to 50 nozzles, 30nozzles, 31 nozzles, 32 nozzles, 33 nozzles, 34 nozzles, 35 nozzles, 36nozzles, 37 nozzles, 38 nozzles or 40 nozzles.

In some aspects, each nozzles of the device configured for epithelialdelivery has a nozzle diameter of at from about from about 1 mm to about3 mm. Each nozzle may have a nozzle diameter of from about 1 mm to about2.5 mm, or from about 2 to 2.5 mm.

In some aspects, the device configured for epithelial delivery to the GItract of a subject contains a dispensable substance having a viscosityof from about 0.8 cP to about 10 cP.

It is to be understood that each and any of the foregoing aspects ofconfiguration 2 are freely combinable to deliver the dispensablesubstance optionally as a jet to tissue of the GI tract of a subject viaepithelial delivery.

It is to be understood that reference to a jet refers to at least onejet, for example, one, two, three, four, five, six, seven, eight or morejets, optionally two jets, three jets or four jets, and that each jetparameter (e.g., jet power, jet velocity, jet stable length, jetpressure, jet force) refers to each said jet, unless expressly indicatedotherwise.

In configuration 3, the device is configured to deliver the dispensablesubstance to tissue of the GI tract of a subject via topical delivery.

In some aspects, the device for topical delivery is configured toprovide an internal pressure of from about 5 psig to about 50 psig. Theinternal pressure may be from about 5 psig to about 30 psig, from about5 psig to about 20 psig, from about 8 psig to about 20 psig, or fromabout 10 psig to about 15 psig.

In some aspects, the device for topical delivery is configured tocontain a dispensable substance at a peak fluid pressure of from about 5psig to about 50 psig. The peak fluid pressure may be from about 5 psigto about 30 psig, from about 5 psig to about 20 psig, from about 8 psigto about 20 psig, or from about 10 psig to about 15 psig.

In some aspects, the device configured for topical delivery releases adispensable substance volume of from about 50 microliters to about 800microliters, about 100 microliters to about 600 microliters, or fromabout 200 microliters to about 400 microliters.

In some aspects, the device configured for topical delivery has from 25to 50 nozzles. The device may have from from 30 to 50 nozzles, 30nozzles, 31 nozzles, 32 nozzles, 33 nozzles, 34 nozzles, 35 nozzles, 36nozzles, 37 nozzles, 38 nozzles or 40 nozzles.

In some aspects, each nozzles of the device configured for topicaldelivery has a nozzle diameter of at from about from about 1 mm to about3 mm. Each nozzle may have a nozzle diameter of from about 1 mm to about2.5 mm, or from about 2 to 2.5 mm.

In some aspects, the device configured for topical delivery to the GItract of a subject contains a dispensable substance having a viscosityof from about 0.8 cP to about 10 cP.

It is to be understood that each and any of the foregoing aspects ofconfiguration 3 are freely combinable to deliver the dispensablesubstance to tissue of the GI tract of a subject via topical delivery.

Based on the present disclosure, the skilled person will appreciate thatthe physical characteristics of the device are assembled to provide theproperties of the device according to the configurations mentionedabove. These physical characteristics are discussed further here:

As discussed herein, the delivery device comprises a housing. An openingin the housing is configured to fluidly connect the dispensablesubstance to an environment outside the housing via the opening.

The delivery device also comprises a drive force generator configured toprovide a force to the dispensable substance to deliver the dispensablesubstance through the opening. The drive force generator can beconfigured to provide an internal pressure as required by the particulardevice configuration. (As described herein, the drive force generatormay comprise a spring, a gas cell, a compressed gas, and a liquid-gasmixture.)

The opening in the housing may comprise a nozzle. There may be multipleopenings with multiple nozzles. The nozzle(s) can be configured toprovide the particular jet properties as required by the particulardevice configuration. The nozzle and drive force generator can beconfigured to provide the particular jet properties as required by theparticular device configuration.

EXAMPLES Example 1—Modelling Device Performance

In this Example, modelling was used to determine the performanceparameters of an ingestible device for delivering a dispensablesubstance.

Model

The driving pressure, for a given point in the dose delivery, is relatedto the delivered liquid volume, and the resulting increase in gasvolume, by equations of state for adiabatic expansion. The velocity(e.g., peak jet velocity, average jet velocity, or minimum jet velocity)through the orifice is in turn given by the driving pressure. This is asteady state approximation in which transient effects of fluidacceleration/deceleration are ignored. In other words, the gas expansionis rapid allowing little time for heat transfer/thermal equilibration tothe surroundings. Thus, this is treated as an adiabatic (no energyloss).

For an adiabatic process, Pressure P and Volume V of a gas are relatedas follows, assuming that fluid (liquid) pressure is equal to gaspressure (frictionless piston).

${\frac{P_{2}}{P_{1}} = \left( \frac{V_{1}}{V_{2}} \right)^{\gamma}},$

where P is pressure, V is volume, and γ is the ratio of specific heats.

Pipe shear pressure is given by the Darcy-Weisbach equation:

${P_{Pipe} = {f\;\frac{\rho\;{Lv}_{o}^{2}}{2d_{o}}}},$

where ρ is the density of a liquid, L is the nozzle length, υ_(o) is thevelocity through the nozzle orifice, d_(o) is the diameter of an nozzleorifice, and f is the Darcy friction factor for pipe flow.

The friction factor for rough pipes is given by:

${\frac{1}{f^{1/2}} = {{- 2.0}{\log\left( {\frac{\epsilon/d_{o}}{3.7} + \frac{2.51}{{Ref}^{1/2}}} \right)}}},$

where ϵ is the pipe surface roughness, and Re is the Reynolds number forthe fluid.

Haaland proposed the following explicit approximation, which differs byless than 2% from Colebrook:

$f^{{- 1}/2} = {\frac{1}{f^{1/2}} = {{- 1.8}{\log\left( {\left( \frac{\epsilon/d_{o}}{3.7} \right)^{1.11} + \frac{6.9}{Re}} \right)}}}$$f = \frac{1}{\left( {{- 1.8}{\log\left( {\left( \frac{\epsilon/d_{o}}{3.7} \right)^{1.11} + \frac{6.9}{Re}} \right)}} \right)^{2}}$

Therefore, pipe pressure is:

$P_{Pipe} = \;\frac{\rho\;{Lv}_{o}^{2}}{2{d_{o}\left( {{- 1.8}{\log\left( {\left( \frac{\epsilon/d_{o}}{3.7} \right)^{1.11} + \frac{6.9}{Re}} \right)}} \right)}^{2}}$

This explicit approximation requires iterative solution if Re isunknown.

Pipe exit and entry losses are assumed as being given by:

P _(Entry)=½C _(Entry)ρ_(l) v ²

P _(Exit)=½C _(Exit)ρ_(l) v ²

Thus, overall pressure drop across the orifice is:

${P_{Orifice} = {{f\frac{\rho\;{Lv}_{o}^{2}}{2d_{o}}} + {\frac{1}{2}\left( {C_{Entry} + C_{Exit}} \right)\rho_{l}v_{o}^{2}}}},$

Where C_(entry) is the coefficient of discharge on entry, and C_(exit)is the coefficient of discharge on exit.

The total flowrate is:

Q=Nπd _(o) ² v _(o),

where Q is the volumetric flow rate through a single orifice.

Accounting for piston friction, the liquid delivery pressure through theorifice is related to the gas pressure as follows. The force balance onthe piston is given by:

${{\frac{\pi}{4}{d_{Piston}^{2}\left( {P_{gas} - P_{Liquid}} \right)}} - F_{Friction}} = {a_{Piston}m_{Piston}}$

Applying a steady state assumption yields:

${\frac{\pi}{4}{d_{Piston}^{2}\left( {P_{gas} - P_{Liquid}} \right)}} - F_{Friction}$

Rearranging, results in:

$P_{Orifice} = {P_{Gas} - \frac{F_{Friction}}{\frac{\pi}{4}d_{Piston}^{2}}}$

The jet impact force is given by the rate of change of the jet momentumat the impact surface:

F=dp/dt=d(mv)/dt=v(dm/dt)+m(dv/dt),

Where p is momentum, v is velocity and m is mass.

Assuming constant jet velocity for a given time step, the dV/dt termgoes to zero, yielding:

F=V(dm/dt), or F=velocity*mass flow rate

F=density*area*velocity{circumflex over ( )}2

F=¼*pi*density*diameter{circumflex over ( )}2*velocity{circumflex over( )}2

The jet power has been shown to correlate with needle-free penetrationand dispersion by:

Power=⅛*pi*density*diameter{circumflex over ( )}2*velcoity{circumflexover ( )}3

Device and Fluid Properties

-   -   Nozzle diameter=0.35 mm    -   Nozzle length=2 mm    -   Number of nozzles=2 or 4    -   Nozzle throat geometry=circular, sharp-edged orifice (similar to        FIG. 6D)    -   Piston diameter=9.6 mm    -   Piston friction=10 N due to one O-ring surrounding the piston    -   Friction pressure loss=about 20 psig    -   Dispensable substance (fluid)=100 mg/mL adalimumab formulation    -   Fluid density=1000 kg/m³    -   Fluid viscosity=7.5 centiPoise    -   Ratios of specific heat (air)=1.4

Results—Initial Internal Pressure of 320 psig—2 Nozzles

The following properties were used in the model.

-   -   Initial internal pressure=320 psig    -   Fluid pressure=about 300 psig (peak; initial)    -   Nozzle pressure=about 300 psig (peak; initial)    -   Initial dose volume of dispensable substance=450 μL    -   Initial gas volume=370 μL

With these parameters, the modelling yielded the results shown in Tables19A-19D (liquid pressure is the same as fluid pressure).

TABLE 19A Gas Liquid Liquid Model Delivered Gas Vol. Pressure Pressurepressure Velocity No. Dose (μL) (μL) (bar) (bar) (psi) (m/s) 1 0 37022.1 20.7 300.0 36.5 2 50 420 18.5 17.1 247.9 33.1 3 100 470 15.8 14.4208.9 30.3 4 150 520 13.7 12.3 178.7 28.0 5 200 570 12.0 10.7 154.7 26.06 250 620 10.7 9.3 135.3 24.3 7 300 670 9.6 8.2 119.3 22.8 8 350 720 8.77.3 160.0 21.5 9 400 770 7.9 6.5 94.7 20.3

TABLE 19B Est. Est. Difference: Model Friction Pressure Pressure P Est.v. P No. Re Factor Drop (Pa) Drop (bar) Set (bar) 1 1.70E+03 7.23E−022.07E+06 20.68 0.00 2 1.54E+03 7.37E−02 1.71E+06 17.09 0.00 3 1.42E+037.51E−02 1.44E+06 14.40 0.00 4 1.31E+03 7.65E−02 1.23E+06 12.32 0.00 51.22E+03 7.78E−02 1.07E+06 10.67 0.00 6 1.14E+03 7.92E−02 9.33E+05 9.330.00 7 1.06E+03 8.05E−02 8.23E+05 8.23 0.00 8 1.00E+03 8.18E−02 7.31E+057.31 0.00 9 9.46E+02 8.31E−02 6.53E+05 6.53 0.00

TABLE 19C Model Jet Impact Jet Impact No. Force (N) Pressure (psi) JetPower (W) 1 0.128 192.7 2.3 2 0.105 158.9 1.7 3 0.089 133.5 1.3 4 0.076113.9 1.1 5 0.065 98.4 0.8 6 0.057 85.8 0.7 7 0.050 75.5 0.6 8 0.04466.9 0.5 9 0.040 59.6 0.4

TABLE 19D Time for Time from Model Flowrate per Total Flowrate DeliveredStart of No. Orifice (m/s) (μL/s) Vol (ms) Dose (ms) 1 3.51E−06 7014.20.0 2 3.18E−06 6368.4 7.47 7.5 3 2.92E−06 5838.1 8.19 15.7 4 2.70E−065392.7 8.90 24.6 5 2.51E−06 5011.8 9.61 34.2 6 2.34E−06 4681.3 10.3244.5 7 2.20E−06 4390.9 11.02 55.5 8 2.07E−06 4133.0 11.73 67.3 91.95E−06 3901.7 12.45 79.7

The minimum (final) fluid pressure is about 95 psig, and the minimum(final) nozzle pressure is about 95 psig. The delivered volume ofdispensable substance is 400 μL, and the final gas volume is 770 μL. Theaverage velocity is 27.0 m/s. The total delivery time is 79.7 ms. Theaverage velocity based on dispense time is 26.1 m/s.

Results—Initial Internal Pressure of 300 psig—2 Nozzles

The following properties were used in the model.

-   -   Initial internal pressure=300 psig    -   Fluid pressure=about 280 psig (peak; initial)    -   Nozzle pressure=about 280 psig (peak; initial)    -   Initial dose volume of dispensable substance=450 μL    -   Initial gas volume=370 μL

With these parameters, the modelling yielded the results shown in Tables20A-20D (liquid pressure is the same as fluid pressure).

TABLE 20A Gas Liquid Liquid Model Delivered Gas Vol. Pressure Pressurepressure Velocity No. Dose (μL) (μL) (bar) (bar) (psi) (m/s) 1 0 37020.7 19.3 280.0 35.2 2 50 420 17.3 15.9 231.2 31.9 3 100 470 14.8 13.4194.6 29.3 4 150 520 12.8 11.5 166.3 27.0 5 200 570 11.3 9.9 143.8 25.16 250 620 10.0 8.7 125.6 23.4 7 300 670 9.0 7.6 110.6 22.0 8 350 720 8.16.8 98.1 20.6 9 400 770 7.4 6.0 87.5 19.5

TABLE 20B Est. Est. Difference: Model Friction Pressure Pressure P Est.v. P No. Re Factor Drop (Pa) Drop (bar) Set (bar) 1 1.64E+03 7.28E−021.93E+06 19.30 0.00 2 1.49E+03 7.43E−02 1.59E+06 15.94 0.00 3 1.37E+037.57E−02 1.34E+06 13.42 0.00 4 1.26E+03 7.71E−02 1.15E+06 11.46 0.00 51.17E+03 7.85E−02 9.91E+05 9.91 0.00 6 1.09E+03 7.99E−02 8.66E+05 8.660.00 7 1.02E+03 8.13E−02 7.63E+05 7.63 0.00 8 9.64E+02 8.26E−02 6.76E+056.76 0.00 9 9.09E+02 8.40E−02 6.03E+05 6.03 0.00

TABLE 20C Model Jet Impact Jet Impact No. Force (N) Pressure (psi) JetPower (W) 1 0.119 179.7 2.10 2 0.098 148.0 1.57 3 0.082 124.2 1.21 40.070 105.9 0.95 5 0.061 91.3 0.76 6 0.053 79.6 0.62 7 0.046 69.9 0.51 80.041 61.8 0.42 9 0.037 55.0 0.36

TABLE 20D Time for Time from Model Flowrate per Total Flowrate DeliveredStart of No. Orifice (m/s) (μL/s) Vol (ms) Dose (ms) 1 3.39E−06 6773.10.0 2 3.07E−06 6146.4 7.74 7.7 3 2.82E−06 5631.4 8.49 16.2 4 2.60E−065198.7 9.23 25.5 5 2.41E−06 4828.6 9.97 35.4 6 2.25E−06 4507.1 10.7146.1 7 2.11E−06 4224.5 11.45 57.6 8 1.99E−06 3973.3 12.20 69.8 91.87E−06 3747.9 12.95 82.8

The minimum (final) fluid pressure is about 87.5 psig, and the minimum(final) nozzle pressure is about 87.5 psig. The delivered volume ofdispensable substance is 400 μL, and the final gas volume is 770 μL. Theaverage velocity is 26.0 m/s. The total delivery time is 82.8 ms. Theaverage velocity based on dispense time is 25.1 m/s.

Results—Initial Internal Pressure of 270 psig—2 Nozzles

The following properties were used in the model.

-   -   Initial internal pressure=270 psig    -   Fluid pressure=about 250 psig (peak; initial)    -   Nozzle pressure=about 250 psig (peak; initial)    -   Initial dose volume of dispensable substance=450 μL    -   Initial gas volume=370 μL        With these parameters, the modelling yielded the results shown        in Tables 21A-21D (liquid pressure is the same as fluid        pressure).

TABLE 21A Gas Liquid Liquid Model Delivered Gas Vol. Pressure Pressurepressure Velocity No. Dose (μL) (μL) (bar) (bar) (psi) (m/s) 1 0 37018.6 17.2 250.0 33.2 2 50 420 15.6 14.2 206.1 30.1 3 100 470 13.3 11.9173.1 27.6 4 150 520 11.6 10.2 147.6 25.4 5 200 570 10.2 8.8 127.4 23.66 250 620 9.0 7.7 111.0 22.0 7 300 670 8.1 6.7 97.5 20.6 8 350 720 7.35.9 86.3 19.3 9 400 770 6.7 5.3 76.7 18.2

TABLE 21B Est. Est. Difference: Model Friction Pressure Pressure P Est.v. P No. Re Factor Drop (Pa) Drop (bar) Set (bar) 1 1.55E+03 7.36E−021.72E+06 17.23 0.00 2 1.41E+03 7.52E−02 1.42E+06 14.21 0.00 3 1.29E+037.68E−02 1.19E+06 11.94 0.00 4 1.19E+03 7.83E−02 1.02E+06 10.18 0.00 51.10E+03 7.98E−02 8.78E+05 8.78 0.00 6 1.03E+03 8.12E−02 7.66E+05 7.660.00 7 9.61E+02 8.27E−02 6.73E+05 6.73 0.00 8 9.02E+02 8.42E−02 5.95E+055.95 0.00 9 8.50E+02 8.57E−02 5.29E+05 5.29 0.00

TABLE 21C Model Jet Impact Jet Impact No. Force (N) Pressure (psi) JetPower (W) 1 0.106 160.2 1.8 2 0.087 131.7 1.3 3 0.073 110.3 1.0 4 0.06293.8 0.8 5 0.054 80.7 0.6 6 0.047 70.2 0.5 7 0.041 61.5 0.4 8 0.036 54.20.3 9 0.032 48.1 0.3

TABLE 21D Time for Time from Model Flowrate per Total Flowrate DeliveredStart of No. Orifice (m/s) (μL/s) Vol (ms) Dose (ms) 1 3.20E−06 6394.90.0 2 2.90E−06 5797.8 8.20 8.2 3 2.65E−06 5306.7 9.01 17.2 4 2.45E−064893.8 9.80 27.0 5 2.27E−06 4540.1 10.60 37.6 6 2.12E−06 4232.7 11.4049.0 7 1.98E−06 3962.1 12.20 61.2 8 1.86E−06 3721.2 13.02 74.2 91.75E−06 3504.9 13.84 88.1

The minimum (final) fluid pressure was about 77 psig, and the minimum(final) nozzle pressure was about 77 psig. The delivered volume ofdispensable substance was 400 μL, and the final gas volume was 770 μL.The average velocity was 24.5 m/s. The total delivery time was 88.1 ms.The average velocity based on dispense time was 23.6 m/s.

Results—Initial Internal Pressure of 220 psig—2 Nozzles

The following properties were used in the model.

-   -   Initial internal pressure=220 psig    -   Fluid pressure=about 200 psig (peak; initial)    -   Nozzle pressure=about 200 psig (peak; initial)    -   Initial dose volume of dispensable substance=450 μL    -   Initial gas volume=370 μL        With these parameters, the modelling yielded the results shown        in Tables 22A-22D (liquid pressure is the same as fluid        pressure).

TABLE 22A Gas Liquid Liquid Model Delivered Gas Vol. Pressure Pressurepressure Velocity No. Dose (μL) (μL) (bar) (bar) (psi) (m/s) 1 0 37015.2 13.8 200.0 29.7 2 50 420 12.7 11.3 164.2 26.8 3 100 470 10.9 9.5137.3 24.5 4 150 520 9.4 8.0 116.6 22.6 5 200 570 8.3 6.9 100.1 20.9 6250 620 7.4 6.0 86.8 19.4 7 300 670 6.6 5.2 75.8 18.1 8 350 720 6.0 4.666.6 16.9 9 400 770 5.4 4.1 58.8 15.9

TABLE 22B Est. Est. Difference: Model Friction Pressure Pressure P Est.v. P No. Re Factor Drop (Pa) Drop (bar) Set (bar) 1 1.38E+03 7.55E−021.38E+06 13.79 0.00 2 1.25E+03 7.73E−02 1.13E+06 11.32 0.00 3 1.14E+037.90E−02 9.47E+05 9.47 0.00 4 1.05E+03 8.07E−02 8.04E+05 8.04 0.00 59.74E+02 8.24E−02 6.90E+05 6.90 0.00 6 9.05E+02 8.41E−02 5.98E+05 5.980.00 7 8.45E+02 8.58E−02 5.22E+05 5.22 0.00 8 7.90E+02 8.75E−02 4.59E+054.59 0.00 9 7.42E+02 8.93E−02 4.06E+05 4.06 0.00

TABLE 22C Model Jet Impact Jet Impact No. Force (N) Pressure (psi) JetPower (W) 1 0.085 127.7 1.3 2 0.069 104.5 0.9 3 0.058 87.2 0.7 4 0.04973.8 0.6 5 0.042 63.1 0.4 6 0.036 54.6 0.4 7 0.032 47.5 0.3 8 0.028 41.60.2 9 0.024 36.6 0.2

TABLE 22D Time for Time from Model Flowrate per Total Flowrate DeliveredStart of No. Orifice (m/s) (μL/s) Vol (ms) Dose (ms) 1 2.86E−06 5710.00.0 2 2.85E−06 5165.8 9.19 9.2 3 2.36E−06 4717.3 10.12 19.3 4 2.17E−064339.2 11.04 30.4 5 2.01E−06 4014.7 11.97 42.3 6 1.87E−06 3731.9 12.9155.2 7 1.74E−06 3482.2 13.86 69.1 8 1.63E−06 3259.4 14.83 83.9 91.53E−06 3058.5 15.83 99.8

The minimum (final) fluid pressure was about 59 psig, and the minimum(final) nozzle pressure was about 59 psig. The delivered volume ofdispensable substance was 400 μL, and the final gas volume was 770 μL.The average velocity was 21.6 m/s. The total delivery time was 99.8 ms.The average velocity based on dispense time was 20.8 m/s.

Results—Initial Internal Pressure of 350 psig—4 Nozzles

The following properties were used in the model.

-   -   Initial internal pressure=350 psig    -   Fluid pressure=about 330 psig (peak; initial)    -   Nozzle pressure=about 330 psig (peak; initial)    -   Initial dose volume of dispensable substance=450 μL    -   Initial gas volume=370 μL

With these parameters, the modelling yielded the results shown in Tables23A-23D (liquid pressure is the same as fluid pressure).

TABLE 23A Gas Liquid Liquid Model Delivered Gas Vol. Pressure Pressurepressure Velocity No. Dose (μL) (μL) (bar) (bar) (psi) (m/s) 1 0 37024.1 22.8 330.0 38.3 2 50 420 20.2 18.8 273.1 34.8 3 100 470 17.3 15.9230.4 31.9 4 150 520 15.0 13.6 197.3 29.5 5 200 570 13.2 11.8 171.1 27.46 250 620 11.7 10.3 149.9 25.6 7 300 670 10.5 9.1 132.4 24.1 8 350 7209.5 8.1 117.8 22.7 9 400 770 8.6 7.3 105.4 21.4

TABLE 23B Est. Est. Difference: Model Friction Pressure Pressure P Est.v. P No. Re Factor Drop (Pa) Drop (bar) Set (bar) 1 1.79E+03 7.16E−022.28E+06 22.75 0.00 2 1.62E+03 7.30E−02 1.88E+06 18.83 0.00 3 1.49E+037.43E−02 1.59E+06 15.88 0.00 4 1.38E+03 7.56E−02 1.36E+06 13.60 0.00 51.28E+03 7.69E−02 1.18E+06 11.80 0.00 6 1.20E+03 7.81E−02 1.03E+06 10.330.00 7 1.12E+03 7.94E−02 9.13E+05 9.13 0.00 8 1.06E+03 8.06E−02 8.12E+058.12 0.00 9 1.00E+03 8.18E−02 7.27E+05 7.27 0.00

TABLE 23C Model Jet Impact Jet Impact No. Force (N) Pressure (psi) JetPower (W) 1 0.141 212.3 2.7 2 0.116 175.2 2.0 3 0.098 147.4 1.6 4 0.084126.0 1.2 5 0.072 109.0 1.0 6 0.063 95.3 0.8 7 0.056 84.0 0.7 8 0.04974.5 0.6 9 0.044 66.6 0.5

TABLE 23D Time for Time from Model Flowrate per Total Flowrate DeliveredStart of No. Orifice (m/s) (μL/s) Vol (ms) Dose (ms) 1 3.68E−06 14722.30.0 2 3.34E−06 13375.8 3.56 3.6 3 3.07E−06 12270.4 3.90 7.5 4 2.84E−0611342.7 4.23 11.7 5 2.64E−06 10550.1 4.57 16.3 6 2.47E−06 9862.8 4.9021.2 7 2.31E−06 9259.3 5.23 26.4 8 2.18E−06 8723.7 5.56 32.0 9 2.06E−068244.0 5.89 37.8

The minimum (final) fluid pressure is about 105.4 psig, and the minimum(final) nozzle pressure is about 105.4 psig. The delivered volume ofdispensable substance is 400 μL, and the final gas volume is 770 μL. Theaverage velocity is 28.4 m/s. The total delivery time is 37.8 ms. Theaverage velocity based on dispense time is 27.5 m/s.

Results—Initial Internal Pressure of 320 psig—4 Nozzles

The following properties were used in the model.

-   -   Initial internal pressure=320 psig    -   Fluid pressure=about 300 psig (peak; initial)    -   Nozzle pressure=about 300 psig (peak; initial)    -   Initial dose volume of dispensable substance=450 μL    -   Initial gas volume=370 μL

With these parameters, the modelling yielded the results shown in Tables24A-24D (liquid pressure is the same as fluid pressure).

TABLE 24A Gas Liquid Liquid Model Delivered Gas Vol. Pressure Pressurepressure Velocity No. Dose (μL) (μL) (bar) (bar) (psi) (m/s) 1 0 37022.1 20.7 300.0 36.5 2 50 420 18.5 17.1 247.9 33.1 3 100 470 15.8 14.4208.9 30.3 4 150 520 13.7 12.3 178.7 28.0 5 200 570 12.0 10.7 154.7 26.06 250 620 10.7 9.3 135.3 24.3 7 300 670 9.6 8.2 119.3 22.8 8 350 720 8.77.3 106.0 21.5 9 400 770 7.9 6.5 94.7 20.3

TABLE 24B Est. Est. Difference: Model Friction Pressure Pressure P Est.v. P No. Re Factor Drop (Pa) Drop (bar) Set (bar) 1 1.70E+03 7.23E−022.07E+06 20.68 0.00 2 1.54E+03 7.37E−02 1.71E+06 17.09 0.00 3 1.42E+037.51E−02 1.44E+06 14.40 0.00 4 1.31E+03 7.65E−02 1.23E+06 12.32 0.00 51.22E+03 7.78E−02 1.07E+06 10.67 0.00 6 1.14E+03 7.92E−02 9.33E+05 9.330.00 7 1.06E+03 8.05E−02 8.23E+05 8.23 0.00 8 1.00E+03 8.18E−02 7.31E+057.31 0.00 9 9.46E+02 8.31E−02 6.53E+05 6.53 0.00

TABLE 24C Model Jet Impact Jet Impact No. Force (N) Pressure (psi) JetPower (W) 1 0.128 192.7 2.3 2 0.105 158.9 1.7 3 0.089 133.5 1.3 4 0.076113.9 1.1 5 0.065 98.4 0.8 6 0.057 85.8 0.7 7 0.050 75.5 0.6 8 0.04466.9 0.5 9 0.040 59.6 0.4

TABLE 24D Time for Time from Flowrate per Total Flowrate Delivered VolStart of Dose Model No. Orifice (m/s) (μL/s) (ms) (ms) 1 3.51E−0614028.4 0.0 2 3.18E−06 12736.9 3.74 3.7 3 2.92E−06 11676.1 4.10 7.8 42.70E−06 10785.3 4.45 12.3 5 2.51E−06 10023.7 4.81 17.1 6 2.34E−069362.7 5.16 22.2 7 2.20E−06 8781.9 5.51 27.8 8 2.07E−06 8266.0 5.87 33.69 1.95E−06 7803.5 6.22 39.8

The minimum (final) fluid pressure is about 94.7 psig, and the minimum(final) nozzle pressure is about 94.7 psig. The delivered volume ofdispensable substance is 400 μL, and the final gas volume is 770 μL. Theaverage velocity is 27.0 m/s. The total delivery time is 39.8 ms. Theaverage velocity based on dispense time is 26.1 m/s.

Results—Summary

A summary of certain data for the ingestible devices with two nozzles isprovided in Table 25 and FIGS. 33-47. “Drive Force Generator:Pre-compressed gas pressure (psig)” is the initial internal pressure,and “liquid pressure” is fluid pressure.

TABLE 25 Drive Force Generator: Pre-compressed gas Peak Liquid Peak JetPeak Jet pressure (psig) Pressure (psig) Velocity (m/s) Power (W) 320300 36.5 2.3 300 280 35.2 2.1 270 250 33.2 1.8 220 200 29.7 1.3

A summary of certain data for the ingestible devices with four nozzlesis provided in Table 26. “Drive Force Generator: Pre-compressed gaspressure (psig)” was the initial internal pressure, and “liquidpressure” is fluid pressure.

TABLE 26 Drive Force Generator: Pre-compressed gas Peak Liquid Peak JetPeak Jet pressure (psig) Pressure (psig) Velocity (m/s) Power (W) 350330 38.3 2.7 320 300 36.5 2.3

Example 2—Jet Velocity Measurements

A high-speed video camera (Photron Fastcam SA3, using 2,000 frames persecond) was used to measure the jet velocities of a dispensablesubstance (water) delivered from devices having different nozzlediameters and nozzle lengths. The receiving medium (externalenvironment) was air. The nozzles were made of MicroFine Green Resin (anABS-like material), using micro-resolution stereolithography (SLA).

The results are shown in Tables 27 and 28. The first 12 nozzles in Table27 correspond to nozzles depicted in FIGS. 6A-6L, respectively.

TABLE 27 Peak Peak (Initial) Jet (Initial) Jet Velocity Velocity NozzleNozzle Internal Avg based on based on Dia. Length Throat Pressuredispensing Jet Dia dispensing Image (mm) (mm) Geometry (psi) time (s) at5 mm time (m/s) processing 0.35 0.5 Rounded 220 0.10 1.0 37.2 38.0 0.350.5 Sharp 220 0.12 1.5 32.1 33.5 0.35 1.5 Rounded 220 0.12 1.0 32.8 34.70.35 1.5 Sharp 220 0.13 0.8 29.7 36.0 0.35 1 Rounded 220 0.12 0.9 31.937.3 0.35 1 Sharp 220 0.12 0.9 32.3 32.0 0.5 0.5 Rounded 220 0.06 1.234.2 34.5 0.5 0.5 Sharp 220 0.07 1.3 28.9 28.0 0.5 1.5 Rounded 220 0.061.1 30.6 36.7 0.5 1.5 Sharp 220 0.07 1.3 27.9 26.5 0.5 1 Rounded 2250.07 1.0 29.2 35.3 0.5 1 Sharp 220 0.08 1.1 25.3 32.0 0.5 DetailedGeometry 220 0.06 1.2 29.7 33.3

TABLE 28 Nozzle Dia Nozzle entrance Avg Dispensing Avg (mm) Shape time(s) Velocity (m/s) 0.35 Rounded 0.115 34.0 0.35 Sharp 0.124 31.4 0.5Rounded 0.061 31.3 0.5 Sharp 0.070 27.4

Example 3—Comparison of PK/PD of Human Insulin Delivered by Subcutaneousor Jet Delivery in the Jejunum Using Euglycemic Clamp Technique in Swine

A study was carried out to compare the pharmacokinetics (PK) andpharmacodynamics (PD) of regular human insulin (NOVOLIN® R) in swinesafter subcutaneous (SC) administration or intra-jejunal (IJ)administration via a single nozzle jet delivery device.

A total of 18 Yorkshire female swine in good health and weighing 60-70kg each were included in this study. Swine were divided into two groupswith 9 animals per group. All 9 animals in group 01 were administered asingle subcutaneous injection of insulin aspart (NOVOLIN® R) (˜40 U) onone side of the neck at a depth of ˜5 mm. A sham surgical laparotomy wasperformed. All 9 animals in group 02 were administrated regular humaninsulin (NOVOLIN® R) (˜40 U) delivered in the proximal jejunum by a jetdelivery device placed by surgical laparotomy. The jet delivery devicewas configured with the single nozzle in an axial orientation. Thedevice was held in place during the laparotomy insertion, and the nozzleoutlet was directed to face the jejunal wall to direct the jet of theNOVOLIN® R to the GI tract. The device was pre-pressurized withcompressed gas to have an internal pressure of about 225 psi, exceptwhere noted.

All animals were fasted overnight prior to the NOVOLIN® Radministration. Swine were divided into two groups with 9 animals pergroup. Prior to NOVOLIN® R administration, the animals wereanesthetized, and two vascular access catheters were placed. In all 18animals, a laparotomy procedure was performed to expose the abdominalcavity. Animals remained under anesthesia during the entire procedurefor the PK/PD study.

All 9 animals in group 01 were administered a single subcutaneousinjection of insulin aspart (NOVOLIN® R) (˜30 U) on one side of the neckat a depth of 5 mm.

All 9 animals in group 02 were dosed with regular human insulin(NOVOLIN® R) in the proximal jejunum by the single nozzle jet deliverydevice placed by surgical laparotomy.

For the laparotomy in group 02, a small segment of the jejunal mucosaand serosa was exposed by midline laparotomy and the jet delivery devicewas inserted through antimesenteric incision. Regular human insulinNOVOLIN® R (˜40 U) was delivered by the jet delivery device, and thebowel and abdominal wall was closed.

For PK/PD blood collections, blood (approximately 3 mL, EDTA) sampleswere collected at −20, −10, 0, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120,150, 180, 210, 240, 270, 300, 330, 360, 390, and 420 minutes afterdosing. Blood samples were kept on wet ice until centrifugation andseparation of plasma. The plasma samples were stored −80° C. on the daysof collection until delivered to AHDC Endocrinology Laboratory atCornell University for insulin analyses. Glucose was monitored everyfive (5) minutes during the study by portable glucose analyzer(StatStrip (SS) hospital glucose monitoring system (Nova Biomedical,Waltham, Mass.)). At each time point, approximate 0.1 mL of blood wasdrawn and immediately placed on a glucose monitoring test strip, and thewhole blood glucose concentration was measured by the SS in triplicate.

A euglycemic clamp procedure (ECP) was employed to comparepharmacokinetics and pharmacodynamics of regular human Insulin (NOVOLIN®R) delivered subcutaneously (SC) in the neck versus intra-jejunally (IJ)by the jet delivery device in the small intestine. ECP was used toquantify the amount of glucose required to maintain normoglycemia afterexogenous bolus of insulin. ECP allowed both the glucose infusion rate(20% dextrose infusion) and total quantity to be calculated, whichrepresented the effect of exogenous insulin on the disposition of bloodglucose. ECP ensured pharmacologic suppression of the production ofendogenous insulin. This study evaluated serum insulin concentration(pg/mL) over time and glucose infusion rate (to maintain a constant ˜85mg/dl BG) over the duration of the ECP (7 hours; 420 min.). The animalswere anesthetized for the entire ECP. The endpoints included acomparison of selected pharmacokinetic parameters for insulin, includingt_(1/2) (min), C_(max) (pg/mL), T_(max) (min) and AUC_(0-420 min)(ng·h/mL), as well as pharmacodynamic parameters such as the rate(mg/kg/min) and amount of glucose (mg/kg) infused.

At the end of the study, all animals were euthanized and animals ingroup 02 underwent gross necropsy for histopathologic evaluation of theproximal jejunum where the NOVOLIN® R was administrated.

Results

FIG. 48 and FIG. 49 show blood insulin levels for each animal. The areaunder the concentration-time curve (AUC_(0-420 min)) of the bloodinsulin, maximum plasma concentration C_(max) (uIU/mL), and time tomaximum plasma concentration (T_(max)) were calculated for each animal.

FIG. 50 and FIG. 51 show blood insulin levels (uIU/mL) and dextroseinfusion rates (mg/min/kg) in SC and IJ administration groups,respectively.

Blood insulin results for SC and IJ administrations are shown in Tables29 and 30, respectively.

TABLE 29 SCAdministration Animal ID 18P15 18P16 18P19 18P20 18P21 18P3418P35 Average* AUC 124486 20281 75580 45338 19729 17811 21211 46348(0-420 min) C_(max)(uIU/mL) 451.00 60.74 354.00 356.60 65.71 59.18 73.34202.94 T_(max)(min) 50 180 105 30 75 120 50 87.14

TABLE 30 IJ Administration Animal ID 18P25 18P14 18P17 18P22 18P23 18P2818P33 18P36 Average* AUC 7677 11588 1389 2229 4024 8797 17046 17075 8728(0-420 min) C_(max)(uIU/mL) 40.93 96.77 5.03 7.96 48.77 85.38 207.96126.39 77.40 T_(max)(min) 20 75 50 90 40 40 40 90 55.63

The mean blood glucose level in SC administration group was 83.5 mg/dL,which was very similar to IJ administration group (89.6 mg/dL). The meandextrose infusion rate was higher in the IJ administration group in thefirst 70 minutes after Novolin® R administration. From 75 minutes to 420minutes post-Novolin® R administration, the mean dextrose infusion ratewas higher in the SC administration group.

The AUC and the maximum plasma concentration C_(max) in the SCadministration group was higher than that of the IJ administrationgroup. The time to maximum plasma concentration (T_(max)) was 55.63minutes in jejunum administration group whereas in the subcutaneousadministration group, T_(max) was 87.14 minutes.

The blood insulin level in animal 18P18 (SC administration group) wassignificantly higher than the rest of the animals in the group. Thereason was unknown. The blood insulin levels post-dosing in animal 18P17and 18P22 were similar to the baseline indicating that IJ administrationof the Novolin® R via the jet delivery device in these animals may nothave been successful.

Example 4—Evaluation of Target Internal Pressure Range for SubmucosalDelivery Using an Ingestible 2-Nozzle Jet Delivery Device by Bench TestJetting of India Ink into Porcine Jejunal Tissue Ex Vivo

A study was conducted to identify the internal pressure range fortrans-epithelial delivery of a drug payload into porcine jejunalsubmucosal tissue ex vivo using India ink as a drug surrogate.

Test Article

India Ink was used in this study.

Ingestible Device Configuration

Each ingestible device used in this study was configured as a capsulecontaining a substance reservoir (volume: 450 μL); two (2) gasreservoirs; a check valve; a floating piston; two (2) nozzles radiallyconfigured 180 degrees apart; a lid at one end of the capsule; and apneumatic control line ((polyetheretherketone (PEEK) tubing) attached tothe lid). The first gas reservoir was positioned behind the substancereservoir and was used to drive the substance (India ink) from thesubstance reservoir. The floating piston separated the substancereservoir from the first gas reservoir. The second gas reservoir waspositioned beneath the lid and used only to open the lid. Although itwas previously demonstrated that a single pressurized gas reservoir canbe used to both open the lid and eject the substance (e.g., drug; datanot shown), the use of two separate gas reservoirs in this study wasintended to demonstrate independent assessment of the action of thetriggering mechanism (lid opening) and the substance ejectionparameters.

Configuration of ingestible device with tissue: Porcine jejunum tissue,previously flash frozen in liquid N₂ and then stored at −80° C., wasthawed and used as the source tissue for testing. In a biological safetycabinet, one side of the jejunum was sealed with a zap strap andstopper. The ingestible device was then inserted into the lumen of thejejunum. Finally, a zap strap fixed the proximal portion of the jejunumto the pneumatic control line.

Device pressurization: An external pressure chamber was connected to anair compressor. Two pressure gauges were used: one was fitted onto theair compressor and a second NIST-certified pressure gauge was placedin-line with the pressure chamber and the air compressor.

The first and second gas reservoirs of each device were pressurizedseparately. To pressurize the first gas reservoir, the device was placedin the pressure chamber and then pressurized to its target internalpressure (200 psig to 350 psig). The pressure chamber was thendepressurized back to ambient atmospheric pressure. The ingestibledevice was then removed from the chamber, after which it maintained thetarget internal pressure by way of the check valve. To pressurize thesecond gas reservoir, the ingestible device control line was directlyattached to the air compressor via an in-line valve. The valve wasturned manually to pressurize the second gas reservoir to 350 psig.

Ex Vivo Jetting Study Protocol and Results

Briefly, a total of five (5) capsules were used in this study and asingle ingestible device was used per test. Prior to testing, eachingestible device (attached to the control line) was filled with a 450μL payload of substance (India ink). The first gas reservoir was thenpressurized with air to its target internal pressure of 200 psig, 250psig, 300 psig or 350 psig, as described above; the pressure was readfrom the in-line NIST gauge, which was in agreement with the pressurereading from the air compressor gauge. At the time of testing, thepressurized device configured with tissue was placed within a blastshield. Then the second gas reservoir (initially at ambient atmosphericpressure) was quickly pressurized to 350 psig, as described above.Pressurizing the second gas reservoir opened the lid, exposing theingestible device nozzles. The internal pressure in the first gasreservoir ejected the India ink from the substance reservoir through thetwo (2) radially-configured nozzles towards the porcine jejunum tissuesurrounding the ingestible device. Pre- and post-deployment deviceweights and diameters were recorded throughout the study to confirmproper device loading/dispensing volumes and pressurization,respectively. The jejunal tissue was then removed from the ingestibledevice and rinsed in 10% neutral buffered formalin (NBF) and deionizedwater for photography. The deployed device was disinfected and driedprior to obtaining its post-pressurization weight.

Pressure tests were performed at 200 psig, 250 psig, 300 psig and 350psig, and visual observations were made after washing the tissue. Theresults are summarized in Table 31. The test result was assigned as PASSif the substance delivered from the device passed through the jejunaltissue without tissue rupture or blow through of ink to the outside ofthe jejunal tissue, or FAIL if the substance delivered from the devicewas not observed to pass through the jejunal tissue or if tissue ruptureor blow through of ink to the outside of the jejunal tissue occurred.

TABLE 31 Pressure Device Test ID (psi) Result Observations 81 200 FAILAll ink deployed from device. No conclusive injection sites could beseen after washing the tissue, and no passing through tissue observed.52 250 PASS Two injection boluses observed, one of which was very faint.Each was markedly smaller than that observed with the 300 psig or 350 gpsi injections. 95 300 PASS All ink deployed from device. India inkobserved inside of the lumen. One ink bolus clearly identified. Secondinjection site lost during excision process. 92 300 ABORT Pressure leakdetected prior to deployment. Test aborted. 84 300 PASS All ink deployedfrom device. Two ink boluses observed. Possible asymmetry noted in bolussizes. Ink deposited in the lumen. 82 350 PASS All ink deployed fromdevice. Two ink boluses observed, with one bolus noticeably smaller thanother.

Example 5—Identification of the Target Internal Pressure Range of anIngestible 2-Nozzle Jet Delivery Device by Evaluating theBioavailability of Adalimumab in Female Yorkshire Pigs

A study was conducted to identify the target internal pressure range ofan ingestible 2-nozzle jet delivery device required to achieve systemicuptake of adalimumab. In this study, the plasma pharmacokinetics ofadalimumab were evaluated in female Yorkshire pigs after intravenous(IV), subcutaneous (SC), or intraduodenal (ID) administration via anendoscopically placed ingestible device.

Test Article

Adalimumab in an aqueous buffer having an adalimumab concentration ofabout 106 mg/mL.

Ingestible Device Configuration

Each ingestible device was configured as a capsule comprising asubstance reservoir; a gas reservoir; a one-way duckbill valve; apiston; two nozzles radially configured 180 degrees apart; two shearpins on opposite sides of the capsule (0.9 mm in diameter, 2.5 mm inlength); and a pneumatic control line (polyetheretherketone (PEEK)tubing) attached at one end of the device to allow for remote pneumatictriggering and release of the test article from the ingestible device.The shear pins were brittle 3D-printed polymer materials having finite(shear) strength sufficient to hold back the internal force in the gasreservoir. To use the ingestible device, the substance reservoir ischarged with the test article; the gas reservoir is charged with a gas(via the one-way duckbill valve) to provide the drive force for ejectingthe test article fluid from the ingestible device as a jet; thepneumatic control line allows for pneumatic triggering and release ofthe test article from the ingestible device; the shear pins restrain theforce provided by the compressed gas and are broken by pneumatic impulseapplied via the pneumatic control line; breakage of the shear pinsallows the stored/applied pressure to open the nozzles quickly and formthe jet.

Shortly before use, each ingestible device was pressurized by placing itin a pressure chamber and attaching the pressure chamber to an aircompressor. The target pressure was set to 320 psig, 270 psig, or 220psig, and the pressurized air was stored in the ingestible device gaschamber and retained via the one-way duckbill valve. After pressurizingthe ingestible device, a seal plug was applied to the duckbill valve andglued with cyanoacrylate.

Nominally, 0.450 mL of test article was loaded into the substancereservoir of the ingestible device using a manual fill procedure. Theingestible device was weighed before and after loading with test articleand the actual amount of test article loaded into the ingestible devicewas determined. The ingestible device loaded with test article was thenshipped to the in vivo study site for use within one week of loadingwith test article. After test article delivery to the study subject wascompleted, the ingestible device was weighed again, and the amount oftest article delivered was determined. Typically, approximately 0.050 mLwas retained in the ingestible device after test article delivery wascompleted. Thus, approximately 0.400 mL of test article was dispensedfrom each ingestible device.

A summary of parameters for the delivery of the test article via theingestible device is provided in Table 32. Initial and final refer tovalues at the beginning and end of the dispensing period for the testarticle, respectively.

TABLE 32 Parameters for test article delivery from ingestible deviceInternal pressure Internal pressure Internal pressure (pressure of pre-(pressure of pre- (pressure of pre- compressed gas): compressed gas):compressed gas): about 320 psig about 270 psig about 220 psigPre-compressed about 370 microliters (initial) gas volume in to about770 microliters (final) ingestible device Nozzle 0.35 mm diameter Nozzlelength   2 mm Nozzle throat circular, sharp-edged orifice geometryPiston diameter  9.6 mm Piston friction 10N (one (1) O-ring on piston)Friction about 20 psig pressure loss Nozzle stand- ≥1.5 mm  off distanceDevice 11.6 mm diameter Device length about 34 to 36 mm Fluid pressureabout 300 psig about 250 psig about 200 psig (peak; initial) (peak;initial) (peak; initial) to about 95 psig to about 77 psig to about 59psig (minimum; final) (minimum; final) (minimum; final Jet velocityabout 36.5 m/s about 33 m/s about 30 m/s (peak; initial) (peak; initial)(peak; initial) to about 20 m/s to about 18 m/s to about 16 m/s(minimum; final) (minimum; final) (minimum; final) Mean jet about 26 toabout 23 to about 20 to velocity 27 m/s 25 m/s 22 m/s Fluid about 80 msabout 88 ms about 100 ms dispensing time (total) Jet impact about 0.13Nabout 0.11N about 0.09 force (peak; initial) (peak; initial) (peak;initial) to about 0.04N to about 0.03N to about 0.02 (minimum; final)(minimum; final) (minimum; final) Jet impact about 193 psig about 160psig about 128 psig pressure (peak; initial) (peak; initial) (peak;initial) to about 60 psig to about 48 psig to about 37 psig (minimum;final) (minimum; final) (minimum; final) Jet power about 2.3 W about 1.8W about 1.3 W (peak; initial) (peak; initial) (peak; initial) to about0.4 W to about 0.3 W to about 0.2 W (minimum; final) (minimum; final)(minimum; final) Jet diameter about 0.35 mm about 0.35 mm about 0.35 mm(initial) (initial) (initial)

In Vivo Study Design

A total of 21 healthy female Yorkshire pigs (Sus scrofa domesticus)having a body weight of 25-30 kg were used in this study. Five (N=5)were used in each of dose Groups 1-3 (intraduodenal (ID) administrationvia an endoscopically placed ingestible device), and three (N=3) wereused in each of dose Group 4 (SC administration) and dose Group 5 (IVadministration). The study design is shown below in Table 33.

TABLE 33 Internal Device Blood Group Dose Dose Pressure or ClinicalCollection # Route N Dose Conc. Volume Observations Time PointsTermination & Necropsy 1 ID 5 40 mg 106 mg/mL 220 PSIG Twice on thePre-dose, 1, 3, Termination and necropsy of the (Device) day of each 6,8, 24, 72, injection site to assess signs of 2 ID 5 40 mg 106 mg/mL 270PSIG endoscopic event, 144, and 240 hematoma and gross lesions (Device)and 24, 72, 144, hours post dose (Day 10 post-dose) 3 ID 5 40 mg 106mg/mL 320 PSIG and 240 hours post (Device) dose 4 SC 3 40 mg 107 mg/mL0.373 mL N/A, animals are to be survived 5 IV 3 40 mg 107 mg/mL 0.373 mL

Animals were housed two per cage and fasted for a minimum of 12 hoursprior to dosing. Food was returned at 4 hours post-dose. Water wassupplied ad libitum. The dosing was as follows: Dose day 1: group 1(n=3), and group 3 (n=2); Dose day 2: group 2 (n=3), and group 1 (n=2);Dose day 3: group 3 (n=3), and group 2 (n=2); Dose day 4: groups 4(n=3), and group 5 (n=3). Following the 240-hour post-dose bloodcollection the animal was euthanized via euthanasia solution IV bolusdose.

Routes of Administration

For intraduodenal (ID) administration, the ingestible device wasattached to an endoscope (Olympus OSF-V60 attached to an Olympus CV60Tower) via a working channel and maneuvered into the pyloric sphincterwith camera visualization to identify the third (inferior/horizontal)part of the duodenum (D3). Following confirmation of placement of theingestible device in the correct region, the endoscope was retracted outof the pyloric sphincter, leaving the ingestible device in the D3 regionof the duodenum. After pausing and observing relaxation of theintestinal walls and obscured vision to the ingestible device, theingestible device was triggered via the pneumatic control line todeliver the test article to the duodenum. After releasing the dose, theendoscope was advanced again for visual observation of the injectionsite. The capsule and endoscope were then retracted out of the body.

For intravenous (IV) administration, the test article was administeredintravenously via bolus dose into the marginal ear vein followed by a 1mL flush with saline if necessary.

For subcutaneous (SC) administration, animals were placed in dorsalrecumbence and the SC injection site asceptically prepared with alcohol.The test article was administered as an SC injection into a “skin tent”on the belly of the pig.

Sampling and Analysis

Plasma samples were collected at pre-dose, 1, 3, 6, 8, 24, 72, 144, and240 hours post-dose in all animals. Each blood sample was collected fromthe pig jugular vein, or other suitable vessel via direct venipuncture,placed into a chilled tube containing K2-EDTA as the anticoagulant, andinverted several times to mix. Blood samples were kept on wet ice untilcentrifugation. Blood samples were centrifuged at a temperature of 4°C., at 3,000×g, for 5 minutes and chilled throughout processing. Plasmawas collected into pre-labeled polypropylene tubes and placed in afreezer set to maintain −60 to −80° C. prior to analysis.

Samples were processed and analyzed by using an adalimumab(anti-TNF-alpha) ELISA kit from Alpha Diagnostics, Inc. (Catalog #200310-AHG). All plasma samples were diluted by 1:100 dilution. Plasmasamples were reanalyzed with a 1:1000 dilution from animals 6287, 6289,6332, 6334, 6336, 6149, 6335, and 6337. Plasma samples close to thelower limit of quantification (LLOQ) were repeated with a 1:5 dilutionfrom animals 6138 and 6137. The final concentrations of adalimumab inthese two animals were lower than previously shown, suggesting thatthese values were at the limits of detection and were not reliable.Therefore, the data from animal 6138 and 6137 were not included in thefinal PK analysis. All data and pharmacokinetic parameters were analyzedand graphed by using GraphPad Prism version 7.00 for Windows, GraphPadSoftware, La Jolla Calif. USA, www.graphpad.com (GraphPad Prism 7). Thearea under the concentration curve (AUC) was calculated with thetrapezoidal rules.

Results

The results are summarized in Table 34. FIG. 52 charts the adalimumabplasma concentration over 10 days for each group.

TABLE 34 2 Nozzle Jet Delivery Device Controls Group 1: Group 2: Group3: Group 4: Group 5: 220 PSIG 270 PSIG 320 PSIG SC IV Route ID ID ID SCIV N 2 4 5 3 3 T_(max) (days) 1 1 1 6 0.13 C_(max) (μg/mL) 0.57 2.275.00 12.60 20.92 AUC 3.32 ± 2.59 8.50 ± 4.16 32.31 ± 8.09 91.87 ± 12.58122.67 ± 7.68 (μg · day/mL) (±SEM) AUC 3.02 ± 2.31 8.19 ± 3.62 32.50 ±8.10 N/A N/A (μg · day/mL) Corrected for dose (±SEM) Bioavailability2.46 ± 1.88 6.68 ± 2.95 26.25 ± 6.60 74.89 ± 10.26 100 over IV^(a)(%)Bioavailability 3.28 ± 2.51 8.92 ± 3.94 35.38 ± 8.82 100 Not calculatedover SC^(a)(%) ^(a)AUC corrected for dose was used to calculatebioavailability.

Example 6—Evaluation of the Bioavailability of Dulaglutide afterIntraduodenal Administration Via an Ingestible 2-Nozzle Jet DeliveryDevice in Female Yorkshire Pigs

A study was performed to determine the plasma pharmacokinetics ofdulaglutide in female Yorkshire pigs after intravenous (IV),subcutaneous (SC), or intraduodenal (ID) administration via anendoscopically placed ingestible device.

Test Article

TRULICITY® (dulaglutide solution) having a dulaglutide concentration of1.5 mg/0.5 mL (i.e., 3 mg/mL) was used in this study. Dulaglutide is along-acting glucagon-like peptide 1 (GLP-1) receptor agonist having amolecular weight of about 63 kDa. The molecule consists of 2 identicaldisulfide-linked chains, each containing a modified human GLP-1 analoguesequence covalently linked to a modified human immunoglobulin G4 (IgG4)heavy chain fragment (Fc) by a small peptide linker. The GLP-1 analogueportion of dulaglutide is approximately 90% homologous to native humanGLP-1 (7-37).

Ingestible Device Configuration

Each ingestible device was configured as a capsule comprising asubstance reservoir; a gas reservoir; a one-way duckbill valve; apiston; two nozzles radially configured 180 degrees apart; two shearpins on opposite sides of the capsule (0.9 mm in diameter, 2.5 mm inlength); and a pneumatic control line (polyetheretherketone (PEEK)tubing) attached at one end of the device to allow for remote pneumatictriggering and release of the test article from the ingestible device.The shear pins were brittle 3D-printed polymer materials having finite(shear) strength sufficient to hold back the internal force in the gasreservoir. To use the ingestible device, the substance reservoir ischarged with the test article; the gas reservoir is charged with a gas(via the one-way duckbill valve) to provide the drive force for ejectingthe test article fluid from the ingestible device as a jet; thepneumatic control line allows for pneumatic triggering and release ofthe test article from the ingestible device; the shear pins restrain theforce provided by the compressed gas and are broken by pneumatic impulseapplied via the pneumatic control line; breakage of the shear pinsallows the stored/applied pressure to open the nozzles quickly and formthe jet.

Shortly before use, each ingestible device was pressurized by placing itin a pressure chamber and attaching the pressure chamber to an aircompressor. The target pressure was set to 320 psig, and the pressurizedair was stored in the ingestible device gas chamber and retained via theone-way duckbill valve. After pressurizing the ingestible device, a sealplug was applied to the duckbill valve and glued with cyanoacrylate.

Nominally, 0.450 mL of test article was loaded into the substancereservoir of the ingestible device using a manual fill procedure. Theingestible device was weighed before and after loading with test articleand the actual amount of test article loaded into the ingestible devicewas determined. The ingestible device loaded with test article was thenshipped to the in vivo study site for use within one week of loadingwith test article. After test article delivery to the study subject wascompleted, the ingestible device was weighed again, and the amount oftest article delivered was determined. Typically, approximately 0.050 mLwas retained in the ingestible device after test article delivery wascompleted. Thus, approximately 0.400 mL of test article was dispensedfrom each ingestible device.

A summary of parameters for the delivery of the test article solutionvia the ingestible device is provided below. Initial and final refer tovalues at the beginning and end of the dispensing period for the testarticle, respectively.

-   -   Internal pressure (pressure of pre-compressed gas): about 320        psig    -   Pre-compressed gas volume in ingestible device: about 370        microliters (initial) to about 770 microliters (final)    -   Nozzle diameter: 0.35 mm    -   Nozzle length: 2 mm    -   Nozzle throat geometry: circular, sharp-edged orifice    -   Piston diameter: 9.6 mm    -   Piston friction: 10 N (one (1) O-ring on piston)    -   Friction pressure loss: about 20 psig    -   Fluid pressure: about 300 psig (peak; initial) to about 95 psig        (minimum; final)    -   Jet velocity: about 36.5 m/s (peak; initial) to about 20 psig        (minimum; final)    -   Mean jet velocity: about 26 to 27 m/s    -   Fluid dispensing time (total): about 80 ms    -   Jet impact force: about 0.13 N (peak; initial) to about 0.04 N        (minimum; final)    -   Jet impact pressure: 193 psig (peak; initial) to about 60 psig        (minimum; final)    -   Jet power: 2.3 W (peak; initial) to about 0.4 W (minimum; final)    -   Jet diameter: about 0.35 mm (initial)    -   Nozzle stand-off distance: >1.5 mm    -   Device diameter: 11.6 mm    -   Device length: about 34 to 36 mm

In Vivo Study Design

A total of 11 healthy female Yorkshire pigs (Sus scrofa domesticus) wereused for the study: n=5 for ID administration, n=3 for IVadministration, and n=3 for SC administration. Each pig weighed betweenabout 25-30 kg at the initiation of the study. A 1.2 mg (˜0.04 mg/kg)dose of the dulaglutide solution was administered to each pig by eitherID administration via the endoscopically placed ingestible device (Group1), IV administration (Group 2), or SC administration (Group 3). Thestudy design is shown below in Table 35.

TABLE 35 Study Design Dose Blood Group Dose Conc. Clinical CollectionTermination & # Route N Dose (mg/mL) Observations Time Points Necropsy 1ID 5 1.2 mg 3 Twice on Pre-dose, At termination, 2 IV 3 (0.4 mL) the dayof 1, 3, 6, 8, necropsy of 3 SC 3 (~0.04 each dose 24, 72, abdominalmg/kg) administration, 144, and region to and 24, 72, 240 hours assesssigns 144, and 240 post dose of hematoma hours post and gross doselesions

Dulaglutide solution was administered at t=0 on the day of dosing. Theanimals were anesthetized with an intramuscular injection of a cocktailcontaining ketamine (approximately 10-20 mg/kg), xylazine (approximately1-2 mg/kg) and atropine (approximately 0.02-0.04 mg/kg). The animalswere intubated and maintained using isoflurane (approximately 3-5% inoxygen 1 to 4 L/min) as necessary until dosing was complete. The animalswere wakened post dose.

Routes of Administration

For intraduodenal (ID) administration, the ingestible device wasattached to an endoscope (Olympus OSF-V60 attached to an Olympus CV60Tower) via a working channel and maneuvered into the pyloric sphincterwith camera visualization to identify the third (inferior/horizontal)part of the duodenum (D3). Following confirmation of placement of theingestible device in the correct region, the endoscope was retracted outof the pyloric sphincter, leaving the ingestible device in the D3 regionof the duodenum. After pausing and observing relaxation of theintestinal walls and obscured vision to the ingestible device, theingestible device was triggered via the pneumatic control line todeliver the test article to the duodenum. After releasing the dose, theendoscope was advanced again for visual observation of the injectionsite. The capsule and endoscope were then retracted out of the body.

For intravenous (IV) administration, the test article was administeredintravenously via bolus dose into the marginal ear vein followed by a 1mL flush with saline if necessary.

For subcutaneous (SC) administration, the test article was administeredinto the dorsal subcutaneous space directly at the base of the pig. Dosesites were gently shaved and circled with marker pen for identifying theinjection site.

Sampling

Each blood sample (˜2.0 mL) were taken from the jugular vein (or othersuitable vessel) of each pig via direct venipuncture. The samples werecollected into chilled tubes with K2EDTA as the anticoagulant, andinverted several times to mix. Blood samples were kept on wet ice untilcentrifugation. The blood samples were centrifuged at a temperature of4° C., at 3,000×g, for 5 minutes. All samples were maintained chilledthroughout processing. Plasma was collected into pre-labeled 2-mLmicrocentrifuge tubes and placed in a freezer set to maintain atemperature of −60° C. to −80° C. until further analysis by ELISA assay.The samples were taken prior to dosing, then again at 1, 3, 6, 8, 24,72, 144, and 240 hours post-dose and sent to an off-site laboratory forbioanalytical analysis. Following the 240 hour post dose bloodcollection, the animals were euthanized via euthanasia solution IV bolusdose.

Analysis

Samples were processed and analyzed by using an enzyme-linkedimmunosorbent assay (ELISA) modified from a validated ELISA method fordetecting dulaglutide in monkey serum (Vahle et al., Toxicol. Pathol.43:1004-1014, 2015).

Briefly, 96-well microtiter plates were coated with mouse anti-human IgG(Fc) antibody (0.5 μg/mL) (Southern Biotech, Birmingham, Ala.) tocapture dulaglutide in swine plasma. Dilutions of dulaglutide standards,quality control samples, and test samples were prepared in 10% swineplasma. Following preparation, the samples were incubated on the coatedplates for 1 h at room temperature. The dulaglutide complex on the platewas bound with a mouse IgG2a kappa anti-GLP-1 antibody (ThermoFisherScientific, Waltham, Mass.) and then detected using a mouse anti-mouseIgG2a-horseradish peroxidase (IgG2a-HPR) (Bethyl, Montgomery, Tex.) withtetramethylbenzidine (TMB) substrate. The standard curve ranged from4.0-0.031 ng/mL, with 0.31 ng/mL being the lowest limit of quantitation.All plasma samples were diluted by 1:10, 1:50, or 1:100 depending on theconcentration of the drug. All data and pharmacokinetic parameters wereanalyzed and graphed using GraphPad Prism version 7.00 for Windows,(GraphPad Software, La Jolla Calif. USA). The area under theconcentration curve (AUC) versus time was calculated with thetrapezoidal rules from the first sample collection time points(pre-dose, time 0) to last time point of sample collection (240 hpost-dose) ((AUC)_(T0-T240 h))).

Non-compartmental analysis was used to determine PK parameters for eachsubject. AUC_(T0-T240 h), half-life, clearance, C_(max) and T_(max) weredetermined for each subject. The bioavailability of dulaglutide via IDadministration (Group 1) in comparison to the IV (Group 2) and SC (Group3) administrations was determined.

Results

The results of the study are shown in Table 36 and in FIGS. 53A-53C andFIG. 54. FIGS. 53A-53C show the dulaglutide concentration in blood overtime after: ID administration via the endoscopically placed ingestibledevice (FIG. 53A); SC administration (FIG. 53B); and IV administration(FIG. 53C). The plasma level of dulaglutide in one animal in Group 1(no. 8487; ID) was below the limit of detection of the ELISA assay. Dataobtained from this animal were excluded from subsequent bioavailabilitydeterminations. Prior to exclusion of these data, the ratio of the areaunder a curve (AUC) of the therapeutic agent concentration in systemiccirculation versus time that was achieved when the drug was administeredby the ID route (AUC_(ID) (ng·hr/mL±SEM)) was 3890.00±94.73.

The bioavailability of dulaglutide via ID administration was determinedrelative to IV or SC administration. The results are shown in FIG. 54.For ID administration, the bioavailability relative to IV administration[(AUC)_(ID/IV)*100%] was about 33%, while the bioavailability relativeto SC administration [(AUC)_(ID/SC)*100%] was about 61%.

TABLE 36 Dulaglutide plasma PK in swine Route ID IV SC N 4 ^(a) 3 3T_(max) (hr) 8  1 6 C_(max) (ng) 70.65 ± 19.18   632.93 ± 49.68 141.3 ±17.09  (AUC)_(T0-T240 h) 4355.86 ± 1094.57 ^(a)  16429.33 ± 600.93 8869± 887.33 ng · hr/mL ± SEM Bioavailability 26.51 ± 6.55% ^(a) 100% 53.98%^(a) relative to IV Bioavailability 49.11 ± 0.08% ^(a) Not calculated100% relative to SC ^(a) The plasma level of one animal was lower thanthe detection limit (see FIG. 53A) and therefore excluded from theAUC_(ID) and AUC_(ID)-based calculations. When this animal is includedin the analysis, the bioavailability relative to SC administration is43.9% [(AUC)_(ID/SC) * 100%], and the bioavailability relative to IVadministration is 23.7% [(AUC)_(ID/IV) * 100%].

Example 7—Identification of the Target Internal Pressure Range of anIngestible 4-Nozzle Jet Delivery Device by Evaluating theBioavailability of Adalimumab after Intraduodenal (ID) Administration toFemale Yorkshire Pigs

A study was conducted to identify the target internal pressure range ofan ingestible 4-nozzle jet delivery device required to achieve systemicuptake of adalimumab. In this study, the plasma pharmacokinetics ofadalimumab were evaluated in female Yorkshire pigs after intraduodenal(ID) administration via an endoscopically placed ingestible device. Theresults were compared with those obtained after administration ofadalimumab via a 2-nozzle jet delivery device, SC or IV (Example 5).

Test Article

Adalimumab in an aqueous buffer having an adalimumab concentration ofabout 106 mg/mL.

Ingestible Device Configuration

Each ingestible device was configured as a capsule comprising asubstance reservoir; a gas reservoir; a one-way duckbill valve; apiston; four nozzles radially configured 90 degrees apart; two shearpins on opposite sides of the capsule (0.9 mm in diameter, 2.5 mm inlength); and a pneumatic control line (polyetheretherketone (PEEK)tubing) attached at one end of the device to allow for remote pneumatictriggering and release of the test article from the ingestible device.The shear pins were brittle 3D-printed polymer materials having finite(shear) strength sufficient to hold back the internal force in the gasreservoir. To use the ingestible device, the substance reservoir ischarged with the test article; the gas reservoir is charged with a gas(via the one-way duckbill valve) to provide the drive force for ejectingthe test article fluid from the ingestible device as a jet; thepneumatic control line allows for pneumatic triggering and release ofthe test article from the ingestible device; the shear pins restrain theforce provided by the compressed gas and are broken by pneumatic impulseapplied via the pneumatic control line; breakage of the shear pinsallows the stored/applied pressure to open the nozzles quickly and formthe jet.

Shortly before use, each ingestible device was pressurized by placing itin a pressure chamber and attaching the pressure chamber to an aircompressor. The target pressure was set to 320 psig or 350 psig, and thepressurized air was stored in the ingestible device gas chamber andretained via the one-way duckbill valve. After pressurizing theingestible device, a seal plug was applied to the duckbill valve andglued with cyanoacrylate.

Nominally, 0.450 mL of test article was loaded into the substancereservoir of the ingestible device using a manual fill procedure. Theingestible device was weighed before and after loading with test articleand the actual amount of test article loaded into the ingestible devicewas determined. The ingestible device loaded with test article was thenshipped to the in vivo study site for use within one week of loadingwith test article. After test article delivery to the study subject wascompleted, the ingestible device was weighed again, and the amount oftest article delivered was determined. Typically, approximately 0.050 mLwas retained in the ingestible device after test article delivery wascompleted. Thus, approximately 0.400 mL of test article was dispensedfrom each jet delivery device.

A summary of parameters for the delivery of the test article via theingestible device is provided in Table 37. Initial and final refer tovalues at the beginning and end of the dispensing period for the testarticle, respectively.

TABLE 37 Parameters for test article delivery from ingestible deviceInternal pressure Internal pressure (pressure of pre- (pressure of pre-compressed gas): compressed gas): about 320 psig about 350 psigPre-compressed about 370 microliters (initial) gas volume in to about770 microliters (final) ingestible device Nozzle diameter 0.35 mm Nozzlelength   2 mm Nozzle stand- ≥1.5 mm  off distance Nozzle throat circularsharp-edged orifice geometry Device diameter 11.6 mm Device length about34 to 36 mm Piston diameter  9.6 mm Piston friction 10N (one (1) O-ringon piston) Friction about 20 psig pressure loss Fluid pressure about 300psig about 330 psig (peak; initial) (peak; initial) to about 95 psig toabout 105 psig (minimum; final) (minimum; final) Jet velocity about 36.5m/s about 38 m/s (peak; initial) (peak; initial) to about 21 m/s toabout 21 m/s (minimum; final) (minimum; final) Mean jet about 26 m/s toabout 26 m/s to velocity 27 m/s 27 m/s Fluid about 40 ms about 40 msdispensing time (total) Jet impact force about 0.13N about 0.14N (peak;initial) (peak; initial) to about 0.04N to about 0.04N (minimum; final)(minimum; final) Jet impact about 193 psig about 212 psig pressure(peak; initial) (peak; initial) to about 60 psig to about 67 psig(minimum; final) (minimum; final) Jet power about 2.3 W about 2.7 W(peak; initial) (peak; initial) to about 0.4 W to about 0.5 W (minimum;final) (minimum; final) Jet diameter about 0.35 mm about 0.35 mm(initial) (initial)

In Vivo Study Design

A total of 9 healthy female Yorkshire pigs (Sus scrofa domesticus)having a body weight of 24-30 kg were used in this study. Five (N=5)were used in dose Group 1 and four (N=4) were used in dose Group 2. Eachdose group received test article via intraduodenal (ID) administration.The study design is shown below in Table 38.

TABLE 38 Internal Blood Group Dose Dose Device Clinical CollectionTermination & # Route N Dose Conc. Pressure Observations Time PointsNecropsy 1 ID 5 40 mg 106 mg/mL 320 PSIG Twice on the Pre-dose, 1,Termination and (Device) day of each 3, 6, 8, 24, necropsy of 2 ID 4 40mg 106 mg/mL 350 PSIG endoscopic 72, 144, and injection site to (Device)event, and 24, 240 hours assess signs of 72, 144, and post dose hematomaand 240 hours gross lesions post dose (Day 10 post dose)

Animals were housed two per cage and fasted for a minimum of 12 hoursprior to dosing. Food was returned at 4 hours post-dose. Water wassupplied ad libitum. The dosing was as follows: Dose day 1: group 1(n=2), and group 2 (n=3); Dose day 2: group 2 (n=3), and group 1 (n=2).Following the 240-hour post-dose blood collection the animals wereeuthanized via intramuscular bolus dose of euthanasia solution.

Intraduodenal (ID) administration was performed as follows. Theingestible device was attached to an endoscope (Olympus OSF-V60 attachedto an Olympus CV60 Tower) via a working channel and maneuvered into thepyloric sphincter with camera visualization to identify the third(inferior/horizontal) part of the duodenum (D3). Following confirmationof placement of the ingestible device in the correct region, theendoscope was retracted out of the pyloric sphincter, leaving theingestible device in the D3 region of the duodenum. After pausing andobserving relaxation of the intestinal walls and obscured vision to theingestible device, the ingestible device was triggered via the pneumaticcontrol line to deliver the test article to the duodenum. Afterreleasing the dose, the endoscope was advanced again for visualobservation of the injection site. The capsule and endoscope were thenretracted out of the body.

Sampling

Each blood sample was collected from the pig jugular vein, or othersuitable vessel via direct venipuncture, placed into a chilled tubecontaining K2-EDTA as the anticoagulant, and inverted several times tomix. Blood samples were kept on wet ice until centrifugation. Bloodsamples were centrifuged at a temperature of 4° C., at 3,000×g, for 5minutes and chilled throughout processing. Plasma was collected intopre-labeled polypropylene tubes and placed in a freezer set to maintain−60 to −80° C. prior to analysis.

Plasma samples were collected at pre-dose, 1, 3, 6, 8, 24, 72, 144, and240 hours post-dose in all animals and sent to an off-site laboratoryfor bioanalytical analysis. Samples were processed and analyzed by usingan adalimumab (anti-TNF-alpha) ELISA kit from Alpha Diagnostics, Inc.(Catalog #200 310-AHG). All plasma samples were diluted by 1:100dilution. Diluted samples were processed in duplicates and the meanOptical Density (O.D.) was measured using a SpectraMax plate reader andutilizing SoftMax Pro software for analysis. The Lower Limit ofQuantification (LLOQ) was calculated by adding 10× the standarddeviation value of the blanks O.D. to the average of the blank standardO.D. values. Mean concentrations of adalimumab were back interpolated toa 4-parameter log fit standard curve and subsequently multiplied by thedilution factor to obtain a final corrected adalimumab concentration.All data and pharmacokinetic parameters were analyzed and graphed byusing GraphPad Prism version 7.00 for Windows, GraphPad Software, LaJolla Calif. USA, www.graphpad.com (GraphPad Prism 7). The area underthe concentration curve (AUC) was calculated with the trapezoidal rules.

Results

The plasma concentrations of adalimumab over time in individual animalsare shown in FIGS. 55A-55B. FIG. 55A represents animals treated withadalimumab after ID administration via the endoscopically placedingestible device having 4 nozzles and an internal pressure of 320 psig.FIG. 55B represents animals treated with adalimumab after IDadministration via the endoscopically placed ingestible device having 4nozzles and an internal pressure of 350 psig.

The PK results were compared to a subset of data from Example 5. Thebioavailability was determined by comparison with Example 5 control arms(SC and IV administration). The results are summarized in Table 39.

TABLE 39 4 Nozzle 2 Nozzle^(a) Controls^(a) Group 1: Group 2: Group 3:Group 4: Group 5: 320 PSIG 350 PSIG 320 PSIG SC IV Route ID ID ID SC IVN 4 4 5 3 3 T_(max) (day) 1 1 1 6 0.13 C_(max) (ug/mL)   3.64 2.63 5.0012.60 20.92 AUC₀₋₁₀ 23.831 ± 5.512 14.603 ± 6.305 32.31 ± 8.09 91.87 ±12.58 122.67 ± 7.68 (ug · day/mL) (±SEM) AUC₀₋₁₀  23.997 ± 5.6147 15.171± 6.522 32.25 ± 8.10 N/A N/A (ug · day/mL) Corrected for Dose (±SEM)Bioavailability 19.560 ± 4.577 12.367 ± 5.317 26.25 ± 6.60 74.89 ± 10.26100 over IV^(b) (±SEM) Bioavailability 26.120 ± 3.731 16.513 ± 4.33435.38 ± 8.82 100 Not calculated over SC^(b) (±SEM) ^(a)Data from Example5 ^(b)AUC corrected for dose was used to calculate bioavailability.

FIG. 56 shows the mean plasma concentration of adalimumab (ng/mL±SEM)over time (0-240 hours) after ID administration via the endoscopicallyplaced ingestible device having: 4 nozzles and an internal pressure of320 psig (Group 1); 4 nozzles and an internal pressure of 350 psig(Group 2); 2 nozzles and an internal pressure of 320 psig (Example 5,Group 3).

Example 8—Evaluation of the Stability and Integrity of Adalimumab afterDelivery Via an Ingestible Device

The effects that various drug dispensing variables, such as nozzlegeometry and delivery pressure, have on the structure and function ofthe target drug adalimumab were evaluated. Delivery pressures up to 300psi and nozzle dimensions down to 0.35 mm diameter were tested.

The experimental design is as follows. Briefly, a drug (adalimumab) wasloaded into a jet device including a piston with a release mechanism. Onthe back side of the piston, pressure was provided by a hand pump, andthe release mechanism was released to release the drug. The end fastenerwas screwed on to secure the nozzle insert and seal the chamber. The jetdevice was operated at a target pressure to dispense the drug into apolypropylene tube for collection and analysis. For the minimum pressuretest, the jet was operated manually by slowly pushing the piston forwardto dispense the drug. For the maximum pressure test, 300 pounds persquare inch gauge (psig) were applied to the jet device, and the drugwas carefully dispensed into a polypropylene collection tube. After eachdose was delivered, the remaining gas pressure was relieved, and thenozzle was cleaned.

Target Binding

Tests were conducted to determine whether certain pressures and nozzlediameters used to deliver adalimumab with an ingestible device wouldresult in physical damage to the drug and affect target drug binding.

Test Method

The drug (adalimumab) was loaded into the ingestible device and firedthrough a nozzle with varying diameters at various pressure conditions.Table 40 summarizes the samples and delivery conditions used.

TABLE 40 Description of Test Articles CODE SAMPLE Description AAdalimumab Standard Adalimumab delivered Delivery from a standardpipette as manufactured. B Very low Pressure 0 psi gauge pressure, loaddevice and dispense T1 Low Pressure 160 psi gauge pressure, 0.5 mmnozzle diameter T2 Target Delivery 230 psi gauge pressure, 0.35 mmnozzle diameter T3 Aggressive Pressure 300 psi gauge pressure, 0.35 mmnozzle diameter NC Negative Control Adalimumab delivered from a standardsyringe as manufactured and pre- processed using Pierce FAb preparationkit C PBS Control PBS Control AlphaLISA AlphaLISA AlphaLISA LOCI Kit KitParts Anti-INFα LOCI Kit

The drug was extracted utilizing the respective dispensing systems andtested by a competitive inhibition assay as described in Velayudhan etal., “Demonstration of functional similarity of proposed biosimilar ABP501 to adalimumab,” BioDrugs 30:339-351, 2016, and Barbeau et. al.,“Application Note: Screening for inhibitors of TNFα/s TNFR1 Bindingusing AlphaScreen™ Technology,” PerkinElmer Technical Note ASC-016,2002.

FIGS. 57A-57B illustrate the general principle of the assay. FIG. 57Ashows binding of anti-TNFα to the TNFα receptor without drug, whereuninhibited binding brings the Donor and Acceptor beads into closeproximity for singlet oxygen transfer detection. FIG. 57B shows bindingof anti-TNFα to TNFα that is inhibited by drug binding to TNFα, thuspreventing binding to anti-TNFα antibodies and proximity oxygen singlettransfer detection.

Drug binding was detected using Luminescent Oxygen Channeling (LOCI™)—acompetitive binding assay. Signal was detected by comparing to anon-drug carrier control and an artificially damaged drug using acommercial FAB fragmentation kit.

Drug function was determined through a competition binding assaycomparing drug binding function for drug dispensed via standard deliverymechanism and drug delivered via the ingestible device with variouspressures.

Results

The jet delivery pressures and nozzle dimensions utilized did not appearto affect the binding or function of the drug. Under the conditionsevaluated in this experiment, the tested pressures did not significantlyinhibit the ability of the drug to bind to the target TNFα as measuredby the LOCI competitive inhibition assay. Table 41 shows the IC₅₀ valuesof adalimumab binding to TNFα under the various conditions tested. FIG.58A is a dose response curve generated after adalimumab (10,000 pg/mL)was dispensed into collection tubes under the conditions described inTable 40.

TABLE 41 IC₅₀ of adalimumab binding to TNFα (10,000 pg/mL) A B T1 T2 T3NC C IC50 0.0007 0.0008 0.0009 0.0009 0.001 0.0045 NA (μg)

Any observable differences between the tested pressures and nozzledimensions were within the standard deviation of the assay (FIG. 58B).The negative control (NC) sample curve was shifted to the right,demonstrating that damaged drug binds less to TNFα, allowing for anincrease of singlet oxygen transfer due to the proximity of the Donorand Acceptor Beads.

Drug Structure

The purpose of this study was to evaluate the effects that nozzlegeometry and delivery pressure have on drug structure when the drug isdispensed from a jet delivery device using different delivery pressuresand nozzle sizes. Structural changes in the jet-delivered drug couldpotentially result in compromised functioning of the drug in vitro.

Test Method

The drug (adalimumab drug substance (DS)) was loaded into the simulatedcapsule jet delivery device and ejected using different pressures andnozzle geometries. Table 42 summarizes the samples and deliveryconditions used.

TABLE 42 Test articles CODE SAMPLE Description A Adalimumab StandardAdalimumab delivered Delivery from a standard pipette as manufactured. BVery low Pressure 0 psi gauge pressure, load device and dispense T1 LowPressure 160 psi gauge pressure, 0.5 mm nozzle diameter T2 TargetDelivery 230 psi gauge pressure, 0.35 mm nozzle diameter T3 AggressivePressure 300 psi gauge pressure, 0.35 mm nozzle diameter NC NegativeControl Adalimumab processed using Pierce FAb preparation kit PPCPre-papain Positive Adalimumab DS, desalted and Control diluted;pre-papain column NC_(gel) Negative Control for Old stock adalimumabprocessed Gel Analysis using Pierce Fab preparation kit; known gelprofile PC_(gel) Positive Control for Old stock adalimumab delivered GelAnalysis from a standard syringe as manufactured; known gel profile

The experimental design flow is shown in FIG. 59 and the assay principleis shown in FIG. 60. Briefly, OD280 nm readings were taken of pre- andpost-dispensed samples, and pre- and post-papain digested adalimumab DS(whole IgG and Fab/Fc fragments, respectively) using a Cytation 5 platereader and Take 3 micro-volume plate. The resulting proteinconcentrations were obtained using an extinction coefficient of 1.4 andGen5 version 3.03.14 program. The samples were then diluted and theprotein profiles were analyzed using non-reducing SDS-PAGE. Proteinbanding patterns of the dispensed samples were compared to that of theunmanipulated drug and the drug artificially damaged (enzymaticallydegraded) via the papain in a commercial Fab fragmentation kit (Pierce™Fab Preparation Kit).

For gel analysis, protein was mixed with non-reducing sample buffer.Samples were not heated. 5 μg of samples and controls were loaded perlane of a SDS-PAGE gel (4% Acrylamide-Bis stacking, 12% resolving; seeTable 43). The gel was electrophoresed at 195 V and stained in R-250Coomassie Blue dye.

TABLE 43 Gel Lane Code Quantity 1 MW Standard  5 μL 2 A 5 μg 3 B 5 μg 4T1 5 μg 5 T2 5 μg 6 T3 5 μg 7 NC 5 μg 8 PPC 5 μg 9 PC_(gel) 5 μg 10NC_(gel) 5 μg

Results

The results are shown in Table 44. None of the jet delivery pressures ornozzle sizes utilized appeared to affect the structure of the drug.

TABLE 44 Code Location 280 Raw 260 Raw 320 Raw 280 260 260/280 mg/mLMean CV (%) A B2 0.947 0.498 0.047 0.95 0.473 0.498 13.865 13.516 3.66B3 0.902 0.478 0.049 0.902 0.451 0.5 13.166 B C2 0.89 0.469 0.046 0.8940.445 0.498 13.053 12.997 0.611 C3 0.885 0.469 0.051 0.886 0.441 0.49812.941 T1 D2 0.884 0.466 0.047 0.889 0.442 0.497 12.985 12.922 0.688 D30.87 0.458 0.047 0.881 0.437 0.497 12.859 T2 E2 0.872 0.461 0.049 0.8740.435 0.497 12.765 12.782 0.193 E3 0.864 0.455 0.046 0.877 0.435 0.49612.8 T3 F2 0.848 0.449 0.051 0.844 0.419 0.496 12.322 12.364 0.472 F30.841 0.443 0.045 0.85 0.421 0.496 12.405 NC C2 0.552 0.333 0.044 0.5370.284 0.529 7.832 7.807 0.463 C3 0.552 0.335 0.05 0.533 0.281 0.5277.781 PPC B2 0.616 0.345 0.053 0.592 0.286 0.483 8.645 8.522 2.037 B30.587 0.327 0.041 0.575 0.28 0.486 8.4 PC_(gel) B2 0.076 0.059 0.0370.039 0.019 0.492 0.57 0.569 0.102 B3 0.076 0.059 0.037 0.039 0.0190.493 0.569 NC_(gel) B2 0.08 0.089 0.044 0.033 0.02 0.604 0.485 0.4860.09 B3 0.084 0.093 0.049 0.033 0.019 0.582 0.486

FIG. 61 shows the results of the gel analysis. All jet-delivered drugsamples showed the same banding pattern as the unmanipulated drug. Nosubunit fragments were visible in their corresponding gel profiles, incomparison to intentionally degraded controls NC and Nc_(gel). Bandingfor controls NC and Nc_(gel) differed from each other. NC showedexpected bands corresponding to Fab and Fc fragments (running at approx.45-50 kda). Nc_(gel) showed a lower MW band, likely due to furtherreduction of adalimumab (digested from a lower starting concentrationthan NC) to Fab heavy and light chain sub-components (approx. 25 kDaeach). Undetermined fragments were also present (see column 8 of FIG.61) as adalimumab was desalted, prior to its loading on the immobilizedpapain column.

No structural changes were evident and there was no physical indicationthat the drug had been inactivated through the dispensing pressures ornozzle sizes employed.

Example 9—Pharmacokinetic and Pharmacodynamic Assessment of TofacitinibCitrate after Oral or Topical Intracecal Administration in a DextranSulfate Sodium (DSS)-Induced Colitis Mouse Model

Study Design

The overall study design is summarized in Table 45. Briefly, at least 10days prior to the start of the study (Day −10), a cohort of male C57BL/6mice underwent surgical implantation of a cecal cannula. Colitis wasinduced in 110 mice (Groups 2-7) by exposure to 3% DSS-treated drinkingwater from Day 0 to Day 5. Five animals (Group 1) served as no-diseasecontrols; the other animals received a single dose of vehicle (Group 2)or tofacitinib citrate suspension containing about 0.5% excipients viaoral gavage (PO; Groups 3 and 4) or intracecal injection via thesurgically implanted indwelling catheter (IC; Groups 5, 6 and 7) once onDay 12 (peak disease status). All animals were weighed daily andassessed visually for the presence of diarrhea and/or blood in stool. Asubset of animals per group was sacrificed for terminal PK collectionsat various time points post-dose. Terminal samples (plasma, cecalcontents, colon contents, cecal tissue and colon tissue) were collectedat terminal sacrifice. All K₂EDTA plasma and tissue homogenate (proximalcolon, cecum and associated lumen contents) were stored at −80° C. untilfurther analysis.

TABLE 45 Description of Treatment Groups Dose Group Number Cecal Colitis(mg/kg) Number of Animals Cannula Induction Treatment (Day 12)¹ Route PKSchedule 1 5 no (a) (a) (a) (a) 24 h post-dose (n = 5) 24 h 2 10 3% DSSin Control 0 PO 1 and 24 h drinking vehicle post-dose water Days (n = 5per 0-5 timepoint) 3 20 Tofacitinib 15 1, 3, 12, 24 h 4 20 citrate 45post-dose 5 20 yes suspension 1 IC (n = 5 per 6 20 3 timepoint) 7 20 10DSS = dextran sulfate sodium; IC = Intracecal injection; PK =Pharmacokinetics; PO = oral gavage (a) Five animals served as no-diseasecontrols. ¹All dose levels are expressed based on tofacitinib citratesalt form.

Sample Bioanalysis

Plasma samples and tissue homogenate (proximal colon, cecum andassociated lumen contents) were assessed for tofacitinib. Briefly,samples were analyzed by LC-MS/MS against matrix-matched standardcurves. Three additional samples were above their respectivequantitation limits, and extrapolated data was reported.

To evaluate pharmacodynamic (PD) effects of tofacitinib in theDSS-induced colitis mouse model, several cytokines involved in theJAK/STAT signaling pathway, i.e., IL-6, GM-CSF, IL-15, IL-2, IL-12,IL-13, TNFα, and INF-γ, were measured in both plasma and colon tissue byELISA.

The study design was complex and involved surgical procedure in adisease model. The PK/PD parameters were derived from limited timepointsand should be considered best estimates only.

All PK/PD concentrations are expressed as active drug moiety (anhydroustofacitinib free base).

Pharmacokinetic Statistical Analysis

PK modeling was performed using mean plasma or tissue concentrations oftofacitinib versus time curves. The following PK parameters werecalculated with a one-compartmental model using Excel software: time tomaximum concentration: T_(max); half-life: t_(1/2), maximumconcentration: C_(max); clearance (Cl), area under theconcentration-time curve from the start of dosing to the lastprotocol-specified time point: AUC_((0-24 h)). The absolute oralbioavailability was estimated to be 74% based on: Xeljanz® (Tofacitinibtablets for oral administration) Prescribing Information RevisedNovember/2012.

Results

Drug Tissue Concentrations

Animals dosed PO with tofacitinib citrate (Groups 3-4) demonstrated thehighest mean plasma tofacitinib concentrations at all timepoints, whilelimited blood exposure was observed in animals treated IC (Groups 5-6)(See FIGS. 62A-62B). Plasma T_(max) occurred between 1.2 and 1.6 hpost-dose in all groups, regardless of dosing route. Colon tissueT_(max) occurred between 1.43 and 1.86 h post-dose in all IC groups, andat 2.25 and 2.33 h post-dose in PO groups (Table 46). At similar doselevels, IC delivery of tofacitinib citrate (IC, 10 mg/kg) resulted in an18-fold higher tofacitinib AUC colon tissue/plasma ratio when comparedto PO delivery (PO, 15 mg/kg) (AUC ratio 193.76 vs. 10.6, respectively;Table 46). Plasma and tissue tofacitinib exposure (AUC_(0-24 h)) arealso shown in FIGS. 63A-63C.

TABLE 46 Pharmacokinetic and pharmacodynamic parameters for tofacitinibover 24 hours after a single dose administration of tofacitinib citratesuspension on Day 12 in DSS-induced colitis mouse model PharmacokineticParameters Pharmacodynamics Group Biological Cmax AUC Tissue/plasma TmaxT_(1/2) Clearance IC₅₀ coverage (h)^(a) Number Route/Dose Matrix (ng/mL)(ng · h/mL) ratio (h) (h) (mL/h) JAK1/3^(b) JAK1/2^(c) JAK2/2^(d) 3PO/15 Plasma 65.5 372.09 10.6 1.61 2.53 656.28 1 0 0 mg/kg Colon tissue552.7 3954.9 2.25 3.23 61.82 12 3 0 4 PO/45 Plasma 467.1 1976.24 7.091.36 1.64 370.7 1 3 1 mg/kg Colon tissue 1774.9 14006.55 2.33 3.4 52.312 12 3 5 IC/1 Plasma 1.3 6.13 253.05 1.56 1.73 2653.91 0 0 0 mg/kgColon tissue 271.7 1551.21 1.61 2.56 10.5 3 3 0 6 IC/3 Plasma 33.2115.45 128.76 1.21 1.19 423.05 1 0 0 mg/kg Colon tissue 2960.2 14865.551.43 2.23 3.29 24 3 3 7 IC/10 Plasma 57.8 223.27 193.76 1.27 1.47 729.173 0 0 mg/kg Colon tissue 7644.9 43261.18 1.86 2.16 3.76 24 12 3 PO =oral gavage; IC = intra-cecal injection; IC₅₀ = half-maximum inhibitoryconcentration; Groups 1 and 2: not applicable ^(a)Concentrations abovethe IC₅₀ over the 24-hour period; ^(b)IC₅₀ of JAK1/3 heterodimer = 56nM^(e) (28.25 ng/mL); ^(c)IC₅₀ of JAK1/2 heterodimer = 406 nM^(e)(204.83 ng/mL); ^(d)IC₅₀ of JAK2/2 homodimer inhibition = 1377 nM^(e)(694.7 ng/mL); ^(e)Meyer et al. (2010) J. Inflamm. 7-41

Cytokines

Inflammatory cytokine IL-6 has been shown to play a critical role in theresponse of uncontrolled intestinal inflammation through JAK1/JAK2 andJAK1/TYK2 signaling pathways (Meyer et al. (2010) J. Inflamm. 7-41).

FIGS. 64A-64B show results obtained for IL-6 in colon tissue on Day 12.IL-6 expression was induced by DSS treatment in both plasma (data notshown) and colon tissue (FIG. 64A) of PO and IC treatment groups;significant induction (p<0.05) was observed on Day 12 when compared withnaïve animals (Group 1).

In plasma, inhibition of IL-6 expression was observed in groups treatedwith tofacitinib citrate via PO or IC administration at 1 h and 3 hpost-treatment; recovery of IL-6 expression (50 to 100%) was observed at12 h and 24 h post-treatment (data not shown).

In colon tissue, inhibition of IL-6 expression was sustained through 24h post-dose in colon tissue in all IC treated groups and in the highdose PO group (45 mg/kg) (FIG. 64B). Recovery from IL-6 inhibition wasobserved in the low dose PO group (15 mg/kg) by 12 h post-dose.

The concentration of GM-CSF (a cytokine activated through stimulation ofthe JAK2/JAK2 pathway) was not significantly different between theDSS-treatment groups and the naïve group, nor was there a significantdifference in GM-CSF levels between IC and PO treatment groups in eitherplasma or colon tissue, despite high exposure of tofacitinib found incolon tissue of IC groups dosed at 3 and 10 mg/kg (data not shown).

Example 10—Topical Intracecal Administration of Therapeutic Antibodiesin a Colitis Animal Model that has Previously Received an AdoptiveT-Cell Transfer

A set of experiments was performed to compare the efficacy of targetedintracecal (IC) anti-mouse-TNFα antibody (a surrogate for adalimumab)and anti-mouse-interleukin (IL) 12p40 antibody (a surrogate ofanti-human-IL12p40 antibody) with systemic intraperitoneal (IP)injection in an adoptive T cell transfer induced chronic colitis mousemodel.

Materials

Test System

-   -   Species/strain: Mice, C57Bl/6 (donors) and RAG2^(−/−)        (recipients; C57Bl/6 background)    -   Physiological state: Normal/immunodeficient    -   Age/weight range at start of study: 6-8 weeks (20-24 g)    -   Animal supplier: Taconic    -   Randomization: Mice were randomized into seven groups of 15 mice        each, and two groups of eight mice each.    -   Justification: T cells isolated from male C57Bl/6 wild type        donors were transferred into male RAG2^(−/−) recipient mice to        induce colitis.    -   Replacement: Animals were not replaced during the course of the        study.

Animal Housing and Environment

-   -   Housing: Mice were housed in groups of 8-15 animals per cage        prior to cannulation surgery. After cannulation surgery,        cannulated animals were single-housed for seven days        post-surgery. After this point, animals were again group-housed        as described above. Non-cannulated animals (Group 9) were housed        at 8 mice per cage. ALPHA-Dri® bedding was used. Prior to        colitis induction (i.e., during the cannulation surgeries),        bedding was changed a minimum of once per week. After colitis        induction, bedding was changed every two weeks, with ¼ of dirty        cage material captured and transferred to the new cage.        Additionally, bedding from Group 9 animals was used to        supplement the bedding for all other groups at the time of cage        change.    -   Acclimation: Animals were acclimatized for a minimum of 7 days        prior to study commencement. During this period, the animals        were observed daily in order to reject animals that presented in        poor condition.    -   Environmental conditions: The study was performed in animal        rooms provided with filtered air at a temperature of 70+/−5° F.        and 50%+/−20% relative humidity. Animal rooms were set to        maintain a minimum of 12 to 15 air changes per hour. The room        was on an automatic timer for a light/dark cycle of 12 hours on        and 12 hours off, with no twilight.    -   Food/water and contaminants: Animals were maintained with        Labdiet 5053 sterile rodent chow. Sterile water was provided ad        libitum.

Test Article: IgG Control

-   -   Name of the Test Article: InVivoMAb polyclonal rat IgG    -   Source: BioXCell, catalog #BP0290    -   Storage conditions: 4° C.    -   Vehicle: Sterile PBS    -   Dose: 0.625 mg/mouse; 0.110 mL/mouse IP and IC    -   Formulation:        -   Formulation Stability: Prepare fresh daily        -   For Group 3: On each day of dosing, dilute stock pAb to            achieve 2.145 mL of a 5.68 mg/mL solution.        -   For Group 4: On each day of dosing, dilute stock pAb to            achieve 2.145 mL of a 5.68 mg/mL solution

Test Article: Anti-IL12 p40

-   -   Name of the Test Article: InVivo MAb anti-mouse IL-12 p40    -   Source: BioXCell, catalog #BE0051    -   Storage conditions: 4° C.    -   Vehicle: Sterile PBS    -   Dose: 0.625 mg/mouse (IP and IC); 0.110 mL/mouse IP and IC    -   Formulation:        -   Formulation Stability: Prepare fresh daily        -   For Group 5: On each dosing day, the stock mAb was diluted            to achieve 1.716 mL of a 5.68 mg/mL solution.        -   For Group 6: On each dosing day, the stock mAb was diluted            to achieve 1.716 mL of a 5.68 mg/mL solution.

Test Article: Anti-TNFα

-   -   Name of the Test Article: InVivoPlus anti-mouse TNFα, clone        XT3.11    -   Source: BioXCell, catalog #BP0058    -   Storage conditions: 4° C.    -   Vehicle: Sterile PBS    -   Dose: 0.625 mg/mouse (IP and IC); 0.110 mL/mouse IP and IC    -   Formulation:        -   Formulation Stability: Prepare fresh daily        -   For Group 7: On each dosing day, the stock mAb was diluted            to achieve 1.716 mL of a 5.68 mg/mL solution.

For Group 8: On each dosing day, the stock mAb was diluted to achieve1.716 mL of a 5.68 mg/mL solution.

Methods

The details of the study design are summarized in Table 47. A detaileddescription of the methods used in this study is provided below.

TABLE 47 Study Design Cell Blood No. Cecal Transfer Schedule CollectionEndpoints Group Animals Cannula (Day 0) Treatment Dose* Route (Days0-42**) (RO) Endoscopy (Day 42) 1 8 YES — — — — — Day 13 Days 14, 3Hours Post 28, 42 Dose: 2 15 0.5 × 10⁶ Vehicle (PBS; IP) — IP; IC IP:3x/week Colon weight/ naïve Vehicle (PBS; IC) IC: QD length, stool 3 15T_(H) cells IgG Control (IP) 625 μg IP: 3x/week score Vehicle (PBS; IC)IC: QD Terminal 4 15 Vehicle (PBS; IP) 625 μg IP: 3x/week collection IgGControl (IC) IC: QD (all groups): 5 15 Anti-IL12p40 (IP) 625 μg IP:3x/week Cecal Contents, Vehicle (PBS; IC) IC: QD Colon 6 15 Vehicle(PBS; IP) 625 μg IP: 3x/week Contents, Anti-IL12p40 (IC) IC: QD Plasma,small 7 15 Anti-TNFα (IP) 625 μg IP: 3x/week intestinal Vehicle (PBS;IC) IC: QD tissue, colon 8 15 Vehicle (PBS; IP) 625 μg IP: 3x/weektissue, mLN, Anti-TNFα (IC) IC: QD and Peyer's Patches 9 8 NO — — — — —— — — *Per mouse; **Test Article was administered in 0.110 mL/animal ICor IP from Day 0~42; IC = intracecal injection; IP = intraperitonealinjection; QD = once a day; RO = Retro-Oribital eye bleed

A cohort of animals underwent surgical implantation of a cecal cannulaat least 10 days to 2 weeks prior to the experiment for the ease ofbolus topical delivery to the cecum. A sufficient number of animalsunderwent implantation to allow for enough cannulated animals to beenrolled in the main study. An additional n=8 animals (Group 9) servedas no surgery/no disease controls.

Colitis was induced by intraperitoneal (IP) injection of 0.5×10⁶CD44/CD62L++ T-cells from C57BL/6 donor mice to male RAG2^(−/−)recipient mice in Groups 2 to 8 on Day 0. The donor cells were processedby first harvesting spleens from 80 C57Bl/6 mice and then isolating theCD44⁻/CD62L⁺ T cells using Miltenyi Magnetic-Activated Cell Sorting(MACS) columns.

To minimize variation due to methods of administration, animals weretreated both by IP injection every third day (3×/wk) and IC injectiononce daily for 42 consecutive days (qdx42d) of either the test articleor the control (vehicle solution or IgG control). Groups were asoutlined in Table 47, also summarized as follows: Group 1=untreated (nodisease controls); Group 2=vehicle [phosphate buffer saline (PBS)](IP)+vehicle (IC); Group 3=IgG (IP)+vehicle (IC); Group 4=vehicle(IP)+IgG (IC); Group 5=anti-IL12p40 (IP)+vehicle (IC); Group 6=vehicle(IC)+anti-IL12p40 (IC); Group 7=anti-TNFα (IP)+vehicle (IC); Group8=vehicle (IP)+anti-TNFα (IC); Group 9=no surgery, untreated(no-cannulation and no-disease controls (sentinel animals for bedding)).Treatment with test article was initiated on Day 0 and was continueduntil Day 42 as outlined in Table 47.

All recipient mice were weighed daily and assessed visually for thepresence of diarrhea and/or bloody stool. The cages were changed everytwo weeks starting on Day 7, with care taken to capture ¼ of dirty cagematerial for transfer to the new cage. On Day 13, blood was collectedvia RO eye bleed, centrifuged, and plasma was aliquoted (50 μL andremaining) and frozen for downstream analysis. The pelleted cells werere-suspended in buffer to determine the presence of T cells by FACSanalysis of CD45⁺/CD4⁺ events.

On Day 13, after dosing, peripheral blood from all surviving mice wasanalyzed by flow cytometry from the presence of CD45+/CD4+ T cells.

The mice underwent high definition video endoscopy on Days 14(pre-dosing; baseline), 28, and 42 (before euthanasia) to assess theextent of colitis severity. Images were captured from each animal at themost severe region of disease identified during endoscopy. Stoolconsistency was scored during endoscopy using the parameters describedherein on Days 14, 18 and 42.

Disease Activity Index (DAI) was calculated using a combination of bodyweight (BW) loss score, colitis score, stool consistency score. The DAI(combined value from 0 to 13) was calculated using colitis score, stoolconsistency score, and BW loss score to provide an overall evaluation ofthe disease intensity (see Table 48). The score from animals withunscheduled death was carried forward to limit any bias that may beintroduced by mortality.

The animals from all groups were euthanized by CO₂ inhalation on Day 42following endoscopy and three hours after dosing. Terminal blood sampleswere collected for bioanalysis of inflammatory cytokines, and tissuessamples were collected and fixed for histopathological evaluation.Plasma obtained from these samples was split into two separatecryotubes, with 50 μL in one tube (Bioanalysis) and the remainder in asecond tube (TBD). The cecum and colon contents were removed and thecontents collected, weighed, and snap frozen in separate cryovials. Themesenteric lymph nodes were collected and flash-frozen in liquidnitrogen. The small intestine were excised and rinsed, and the mostdistal 2-cm of ileum was placed in formalin for 24 hours and thentransferred to 70% ethanol for subsequent histological evaluation. ThePeyer's patches were collected from the small intestine, and wereflash-frozen in liquid nitrogen. The colon was rinsed, measured,weighed, and then trimmed to 6-cm in length and divided into 5 pieces asdescribed in the above Examples. The most proximal 1-cm of colon wasseparately weighed, and flash-frozen for subsequent bioanalysis (PK) oftest article levels. Of the remaining 5-cm of colon, the most distal andproximal 1.5-cm sections were each placed in formalin for 24 hours andthen transferred to 70% ethanol for subsequent histological evaluation.The middle 2-cm portion was bisected longitudinally, and each piece wasweighed, placed into two separate cryotubes, and snap frozen in liquidnitrogen; one of the samples was used for cytokine analysis and theother was used for myeloperoxidase (MPO) analysis. All plasma and frozencolon tissue samples were stored at −80° C. until used for endpointanalysis.

The colon weight (mg) to length (cm) ratio was calculated for individualmice.

A more detailed description of the protocols used in this study aredescribed below.

Cecal Cannulation

Animals were placed under isoflurane anesthesia, and the cecum wasexposed via a mid-line incision in the abdomen. A small point incisionwas made in the distal cecum through which 1-2 cm of the cannula wasinserted. The incision was closed with a purse-string suture using 5-0silk. An incision was made in the left abdominal wall through which thedistal end of the cannula was inserted and pushed subcutaneously to thedorsal aspect of the back. The site was washed copiously with warmedsaline prior to closing the abdominal wall. A small incision was made inthe skin of the back between the shoulder blades, exposing the tip ofthe cannula. The cannula was secured in place using suture, wound clips,and tissue glue. All of the animals received 1 mL of warm sterile saline(subcutaneous injection) and were monitored closely until fullyrecovered before returning to the cage. All animals receivedbuprenorphine at 0.6 mg/kg BID for the first 3 days, and Baytril at 10mg/kg QD for the first 5 days following surgery.

Disease Induction

Colitis was induced on Day 0 in male RAG2^(−/−) mice by IP injection(200 μL) of 0.5×10⁶ CD44⁻/CD62L⁺ T cells (in PBS) isolated and purifiedfrom C57Bl/6 recipients.

Donor Cell Harvest

Whole spleens were excised from C57Bl/6 mice and immediately placed inice-cold PBS. The spleens were dissociated to yield a single cellsuspension and the red blood cells were lysed. The spleens were thenprocessed for CD4⁺ enrichment prior to CD44⁻CD62L⁺ sorting by MACS.

Dosing

See Table 47.

Body Weight and Survival

The animals were observed daily (morbidity, survival, presence ofdiarrhea and/or bloody stool) in order to assess possible differencesamong treatment groups and/or possible toxicity resulting from thetreatments. Animals were weighed daily and their percent body weightrelative to Day 0 was calculated.

Animals Found Dead or Moribund

The animals were monitored on a daily basis and those exhibiting weightloss greater than 30% were euthanized, and did not have samplescollected.

Endoscopy

Each mouse underwent video endoscopy on Days 14 (pre-dosing; baseline),28, and 42 (before euthanasia) using a small animal endoscope (KarlStorz Endoskope, Germany), under isoflurane anesthesia. During eachendoscopic procedure, still images as well as video were recorded toevaluate the extent of colitis and the response to treatment.Additionally, an image from each animal at the most severe region ofdisease identified during endoscopy was captured. Colitis severity wasscored using a 0-4 scale (0=normal; 1=loss of vascularity; 2=loss ofvascularity and friability; 3=friability and erosions; 4=ulcerations andbleeding). Additionally, stool consistency was scored during endoscopyusing the scoring system described herein.

Sample Collection

Terminal blood (plasma and cell pellet), Peyer's patches (Groups 1-8only), small intestine and colon mLN (Groups 1-8 only), cecum contents,colon contents, small intestine, and colon were collected at euthanasia,as follows.

Blood: Terminal blood was collected by cardiac puncture and plasmagenerated from these samples. The resulting plasma was split into twoseparate cryotubes with 50 μL in one tube (Bioanalysis), and theremainder in a second tube (TBD).

Mesenteric Lymph Nodes: The mesenteric lymph nodes were collected,weighed, snap-frozen in liquid nitrogen, and stored at −80° C.

Small Intestine: The small intestine was excised and rinsed, and themost distal 2-cm of ileum will be placed in formalin for 24 hours andthen transferred to 70% ethanol for subsequent histological evaluation.

Peyer's Patches: The Peyer's patches were collected from the smallintestine. The collected Peyer's patches were weighed, snap-frozen inliquid nitrogen, and stored at −80° C.

Cecum/Colon Contents: The cecum and colon were removed from each animaland contents collected, weighed, and snap-frozen in separate cryovials.

Colon: Each colon was rinsed, measured, weighed, and then trimmed to6-cm in length and divided into 5 pieces as outlined herein. The mostproximal 1-cm of colon was separately weighed, and snap frozen forsubsequent bioanalysis (PK) of test article levels. Of the remaining5-cm of colon, the most distal and proximal 1.5-cm sections were placedin formalin for 24 hours and then transferred to 70% ethanol forsubsequent histological evaluation. The middle 2-cm portion was bisectedlongitudinally, and each piece weighed, placed into two separatecryotubes, and snap-frozen in liquid nitrogen; one of these samples wasused for cytokine analysis and the other sample was used formyeloperoxidase analysis.

Cytokine Levels in Colon Tissue

Cytokine levels (IFNγ, IL-2, IL-4, IL-5, IL-1β, IL-6, IL-12 p40, andTNFα) were assessed in colon tissue homogenate (all groups) by multiplexanalysis. Myeloperoxidase levels were assessed by ELISA in colon tissuehomogenate (all groups).

Histopathology

Ileum, proximal colon, and distal colon samples from seventy-one micewere fixed in 10% neutral buffered formalin. Samples were trimmed intothree cross sections per portion and processed routinely into two blocksper animal (ileum in one block, proximal and distal colon in a secondblock). One slide from each block was sectioned at approximately 5microns and stained with hematoxylin and eosin (H&E). Glass slides wereevaluated with light microscopy by a board-certified veterinarypathologist. Ileum, proximal colon, and distal colon samples were scoredindividually. Lesions in H&E-stained samples were given a severity score0-51 (0=not present/normal, 1=minimal, <10% of tissue affected; 2=mild,10-25% of tissue affected; 3=moderate, 26-50% of tissue affected;4=marked, 51-79% of tissue affected; 5=severe, >75% of the tissueaffected). Inflammation, crypt damage, erosion, and hyperplasia scoreswere added together to determine a sum colitis score for each sample.

Lymphocyte counts were performed in a subset of samples: proximal anddistal colon from Groups 2 (vehicle), 7 (anti-TNF-alpha IP; vehicle IC),and 8 (anti-TNF-alpha IC; vehicle IP). In each piece of tissue, arandomly identified site was divided into approximately four segmentsextending from the lumen to the muscularis mucosae; 100 μm2 fields wereused in the proximal colon, and 50 μm2 fields were used in the distalcolon due to the differences in mucosal thickness. Using H&E-stainedslides, the number of cells with lymphocyte morphology (small roundnucleus with condensed chromatin) were counted within the overlyingsurface epithelium, in each field from lumen to muscularis mucosae, andwithin a 100 μm2 field surrounding an adjacent submucosal blood vessel.

Statistical Analysis

As presented in the figures, non-parametric data was analyzed byKruskal-Wallis test with Dunn's multiple comparisons test used tocompare all groups to one another and individual pair-wise comparisonswas analyzed by Mann Whitney U-Test. All statistical analyses wereperformed using GraphPad Prism 7 (La Jolla, Calif.).

Results

Survival

The observed mortality rate was within the expected range given thedesign including surgical intervention, T-cell transfer inimmunologically compromised animals followed by chronic development ofcolitis over a 6-week study period (Ostanin D V et al. Am J PhysiolGastrointest Liver Physiol. 2009, 296(2):G135-G146).

The survival of animals was compared; no significant difference insurvival rate was found in treatments of anti-IL12p40 and anti-TNFα witheither route of administration compared to vehicle or IgG controls(p>0.08, log-rank; Kaplan-Meier). The timing of animal deaths did notcorrespond to changes in efficacy endpoints, such as body weight, thatwere evaluated longitudinally. As noted above, changes in DAI scorewhich includes, BW loss, stool consistency and colitis severity werecarried forward to limit any bias that may be introduced by mortality.

Colon Weight:Length Ratio

The mean colon weight:length ratio was significantly elevated in vehiclecontrol animals (Group 2) compared to naïve (Group 1); no othersignificant differences in mean colon weight:length ratio were observed.

Disease Activity Index

The Disease Activity Index was determined in each mouse using a totalscore from the scoring system depicted in Table 48.

TABLE 48 Disease Activity Index scoring system Disease Activity IndexDescription Score Colitis Severity Normal 0 Loss of vascularity 1 Lossof vascularity and friability 2 Friability and erosions 3 Ulcerationsand bleeding 4 Stool Consistency Normal 0 Loose stool, soft, staying inshape 1 Abnormal form with excess moisture 2 Watery or diarrhea 3 Bloodydiarrhea 4 Body Weight Loss (%) X < 0% or gain weight 0 2% ≤ X < 5% 1 5%≤ X < 10% 2 10% ≤ X < 15% 3 15% ≤ X < 20% 4 20% ≤ X < 25% 5 25% ≤ X <30% 6 X ≥ 35% 7 Total Score 15

The data in FIG. 65 show that mice intracecally administered anti-TNFαantibody (Group 8) had decreased disease activity index (DAI) ascompared to mice intraperitoneally administered anti-TNFα antibody(Group 7) at Day 42 of the study. The data in FIG. 67 show that miceintracecally administered anti-IL12 p40 antibody (Group 6) had decreaseddisease activity index (DAI) as compared to mice intraperitoneallyadministered anti-IL12 p40 antibody (Group 5) at Day 28 and Day 42 ofthe study.

Inflammatory Cytokines in Colonic Tissue

The concentration of inflammatory cytokines was evaluated in the colonictissue in vehicle or IgG control groups.

A significant reduction of inflammatory cytokines, including IL 17A,IL-4, TNFα, and IL-22, were found in groups treated with anti-TNFα (IC(Group 8) or IP (Group 7)) when compared with vehicle (IP/IC) control orits respective IgG controls (IC or IP) in colon tissue (FIG. 66). Micetreated with anti-TNFα antibody IC (Group 8) had decreased levels ofTNFα, IL-17A, and IL-4 in colonic tissue as compared to the levels incolonic tissue of mice treated with anti-TNFα IP (Group 7) when assessedat Day 42 of the study.

A significant reduction of IL-22, IL-6, IL17A, TNFα, IL-1b, and IFNγcytokine was found in groups treated with anti-IL12p40 (IP or IC) whencompared with vehicle (IP/IC) control in colon tissue (FIG. 68). Miceintracecally administered anti-IL12 p40 antibody (Group 6) had decreasedlevels of IFNK, IL-6, IL-17A, TNFα, IL-22, and IL-1b in colonic tissueas compared to the levels in colonic tissue in vehicle-administeredcontrol mice (Group 2).

Body Weight Loss

Treatments with either systemic (IP) or topical (IC) administration ofan anti-TNFα antibody or anti-IL12p40 antibody led to a significantdecrease in body weight (BW) loss over time from Day 0 to Day 42.

The change in body weight over the course of the experiment from Day 0through Day 42 is shown in FIGS. 69A and 69B. No apparent signs ofdisease were observed within the first week after induction of colitis.In control groups treated with PBS vehicle and/or IgG, BW loss did notbegin until Days 14 through 16 and continued in the 3rd and 4th weekfollowing transfer during the acute phase. The weight loss wasmaintained until study termination on Day 42. Administration ofanti-TNFα antibody or anti-IL12p40 antibody through either IP or IC hada significant reduction in AUC of the BW loss (%) from Day 0 to Day 42along with the weight increase maintained from Day 21 to Day 42 (FIGS.69A and 69B). Overall, intracecal administration of anti-IL12p40antibody had the earliest recovery of weight loss and most significantreduction in overall BW loss from Day 0 Day 42 in comparison to thevehicle control group amount of all treatment groups (FIG. 69B).

Histopathology Colitis Score

Lesions of ileitis and colitis, including inflammation, crypt damage,occasional erosions, and epithelial hyperplasia, were induced with theT-cell transfer in this model. Lesions were the least severe in ileumsections and the most severe in the proximal colon. Both IP and ICadministration of anti-IL12p40 and anti-TNFα resulted in a reduction insum ileitis/colitis scores compared to PBS vehicle control. Targeted ICanti-TNFα treatment showed a significant improvement in the meanhistopathologic score when compared with the vehicle controls given byeither route (IP or IC) in proximal and distal colon tissues (FIG. 70).

Lymphocyte Counts

Targeted IC anti-TNFα treatment showed the greatest magnitude oflymphocyte reductions in all counted fields, from inner lumen tosubmucosa of proximal colon when compared to the vehicle control group(Group 8 vs. Group 2, P<0.05*, FIG. 69A). A similar trend in lymphocytecount reductions was found in the distal colon, although to a lesserdegree. Results are shown in FIGS. 71A-71D. Mean counts and scores forall fields were generally the highest in vehicle-treated animals (Group2, data not shown) and lower in those given anti-TNFα by IP (Group 7,data not shown) or IC (Group 8, FIG. 71B).

Thus, significantly reduced body weight loss (%), decreased DiseaseActivity Index, improved histological score and reduced tissueinflammatory cytokines were found in animals receiving targeted (IC)anti-TNFα antibody when compared with vehicle controls. Targeted ICdelivery was significantly more efficacious when compared to systemic(IP) anti-TNFα antibody in end points of total histologic score andlymphocyte count from inner lumen to submucosa of proximal colon.

Example 11—Evaluation of the Bioavailability of Semaglutide afterIntraduodenal Administration Via an Ingestible 2-Nozzle Jet DeliveryDevice in Female Yorkshire Pigs

A study was performed to determine the plasma pharmacokinetics ofsemaglutide in female Yorkshire pigs after intravenous (IV),subcutaneous (SC), or intraduodenal (ID) administration via anendoscopically placed ingestible device.

Test Article

OZEMPIC® (semaglutide solution) having a semaglutide concentration of1.34 mg/mL was used in this study.

Ingestible Device Configuration

Each ingestible device was configured as a capsule comprising asubstance reservoir; a gas reservoir; a one-way duckbill valve; apiston; two nozzles radially configured 180 degrees apart; two shearpins on opposite sides of the capsule (0.9 mm in diameter, 2.5 mm inlength); and a pneumatic control line (polyetheretherketone (PEEK)tubing) attached at one end of the device to allow for remote pneumatictriggering and release of the test article from the ingestible device.The shear pins were brittle 3D-printed polymer materials having finite(shear) strength sufficient to hold back the internal force in the gasreservoir. To use the ingestible device, the substance reservoir ischarged with the test article; the gas reservoir is charged with a gas(via the one-way duckbill valve) to provide the drive force for ejectingthe test article fluid from the ingestible device as a jet; thepneumatic control line allows for pneumatic triggering and release ofthe test article from the ingestible device; the shear pins restrain theforce provided by the compressed gas and are broken by pneumatic impulseapplied via the pneumatic control line; breakage of the shear pinsallows the stored/applied pressure to open the nozzles quickly and formthe jet.

Shortly before use, each ingestible device was pressurized by placing itin a pressure chamber and attaching the pressure chamber to an aircompressor. The target pressure was set to 320 psig, and the pressurizedair was stored in the ingestible device gas chamber and retained via theone-way duckbill valve. After pressurizing the ingestible device, a sealplug was applied to the duckbill valve and glued with cyanoacrylate.

Nominally, 0.450 mL of test article was loaded into the substancereservoir of the ingestible device using a manual fill procedure. Theingestible device was weighed before and after loading with test articleand the actual amount of test article loaded into the ingestible devicewas determined. The ingestible device loaded with test article was thenshipped to the in vivo study site for use within one week of loadingwith test article. After test article delivery to the study subject wascompleted, the ingestible device was weighed again, and the amount oftest article delivered was determined. Typically, approximately 0.050 mLwas retained in the ingestible device after test article delivery wascompleted. Thus, approximately 0.400 mL of test article was dispensedfrom each ingestible device.

A summary of parameters for the delivery of the test article solutionvia the ingestible device is provided below. Initial and final refer tovalues at the beginning and end of the dispensing period for the testarticle, respectively.

-   -   Internal pressure (pressure of pre-compressed gas): about 320        psig    -   Pre-compressed gas volume in ingestible device: about 370        microliters (initial) to about 770 microliters (final)    -   Nozzle diameter: 0.35 mm    -   Nozzle length: 2 mm    -   Nozzle throat geometry: circular, sharp-edged orifice    -   Piston diameter: 9.6 mm    -   Piston friction: 10 N (one (1) O-ring on piston)    -   Friction pressure loss: about 20 psig    -   Fluid pressure: about 300 psig (peak; initial) to about 95 psig        (minimum; final)    -   Jet velocity: about 36.5 m/s (peak; initial) to about 20 psig        (minimum; final)    -   Mean jet velocity: about 26 to 27 m/s    -   Fluid dispensing time (total): about 80 ms    -   Jet impact force: about 0.13 N (peak; initial) to about 0.04 N        (minimum; final)    -   Jet impact pressure: 193 psig (peak; initial) to about 60 psig        (minimum; final)    -   Jet power: 2.3 W (peak; initial) to about 0.4 W (minimum; final)    -   Jet diameter: about 0.35 mm (initial)    -   Nozzle stand-off distance: >1.5 mm    -   Device diameter: 11.6 mm    -   Device length: about 34 to 36 mm

In Vivo Study Design

A total of 11 healthy female Yorkshire pigs (Sus scrofa domesticus) wereused for the study: n=5 for ID administration, n=3 for IVadministration, and n=3 for SC administration. Each pig weighed betweenabout 25-30 kg at the initiation of the study. A fixed dose of 0.5 mgsemaglutide per pig (˜0.02 mg/kg) was administered intraduodenally (ID)via the endoscopically placed ingestible device (Group 1); a 0.02 mg/kgdose was administered to each pig in the IV (Group 2) and SC (Group 3)dose groups. The study design is shown below in Table 49.

TABLE 49 Study Design Dose Blood Dose Conc. Clinical CollectionTermination & Group # Route N Dose (mg/mL) Observations Time PointsNecropsy 1 ID 5 0.5 mg 1.34 2 IV 3 (~0.02 Twice on the Pre-dose, Attermination, mg/kg) day of each 1, 3, 6, 8, necropsy of 3 SC 3 (~0.02dose 24, 72, abdominal mg/kg) administration, 144,and region to and 24,72, 240 hours assess signs 144, and 240 post dose of hematoma hours postand gross dose lesions

Semaglutide solution was administered at t=0 on the day of dosing. Theanimals were anesthetized with an intramuscular injection of a cocktailcontaining ketamine (approximately 10-20 mg/kg), xylazine (approximately1-2 mg/kg) and atropine (approximately 0.02-0.04 mg/kg). The animalswere intubated and maintained using isoflurane (approximately 3-5% inoxygen 1 to 4 L/min) as necessary until dosing was complete. The animalswere wakened post dose.

Routes of Administration

For intraduodenal (ID) administration, the ingestible device wasattached to an endoscope (Olympus OSF-V60 attached to an Olympus CV60Tower) via a working channel and maneuvered into the pyloric sphincterwith camera visualization to identify the third (inferior/horizontal)part of the duodenum (D3). Following confirmation of placement of theingestible device in the correct region, the endoscope was retracted outof the pyloric sphincter, leaving the ingestible device in the D3 regionof the duodenum. After pausing and observing relaxation of theintestinal walls and obscured vision to the ingestible device, theingestible device was triggered via the pneumatic control line todeliver the test article to the duodenum. After releasing the dose, theendoscope was advanced again for visual observation of the injectionsite. The capsule and endoscope were then retracted out of the body.

For intravenous (IV) administration, the test article was administeredintravenously via bolus dose into the marginal ear vein followed by a 1mL flush with saline if necessary.

For subcutaneous (SC) administration, the test article was administeredinto the dorsal subcutaneous space directly at the base of the pig. Dosesites were gently shaved and circled with marker pen for identifying theinjection site.

Sampling

Each blood sample (˜2.0 mL) were taken from the jugular vein (or othersuitable vessel) of each pig via direct venipuncture. The samples werecollected into chilled tubes with K2EDTA as the anticoagulant, andinverted several times to mix. Blood samples were kept on wet ice untilcentrifugation. The blood samples were centrifuged at a temperature of4° C., at 3,000×g, for 5 minutes. All samples were maintained chilledthroughout processing. Plasma was collected into pre-labeled 2-mLmicrocentrifuge tubes and placed in a freezer set to maintain atemperature of −60° C. to −80° C. until further analysis. The sampleswere taken prior to dosing, then again at 1, 3, 6, 8, 24, 72, 144, and240 hours post-dose and sent to an off-site laboratory for bioanalyticalanalysis. Following the 240 hour post dose blood collection, the animalswere euthanized via euthanasia solution IV bolus dose.

Analysis

Samples were processed and analyzed by using a modified LC-MS/MS method(Kapitza, C. et al., J. Clin. Pharm. (2015) 55(5) pp. 497-504) toquantify in swine plasma in the concentration range 5-500 (for BLQsamples) and 50-1000 ng/mL to quantify in swine plasma. Liraglutide wasused as an internal standard (IS). The analysis was carried out using aWaters Xevo-TQ-S LC-MS/MS spectrometer monitoring positive ions in theMRM mode with mass transitions m/z 1029.468>136.124 Da (semaglutide) andm/z 938.9>1266.99 Da (IS), respectively. The LC system was a WatersAcquity™ UPLC® system and the LC column an InfinityLab Poroshell 120Bonus-RP, 2.1×150 mm, 2.7 μm. Quantification was performed by peak areasand weighted linear regression (1/x²). The lower limit of quantification(LLOQ) for semaglutide was 5 ng/mL. All data and pharmacokineticparameters were analyzed and graphed using GraphPad Prism version 7.00for Windows, (GraphPad Software, La Jolla Calif. USA). The area underthe concentration curve (AUC) versus time was calculated with thetrapezoidal rules from the first sample collection time points(pre-dose, time 0) to last time point of sample collection (240 hpost-dose) ((AUC)_(T0-T240 h))). Non-compartmental analysis was used todetermine PK parameters for each subject. AUC_(T0-T240 h), C_(max) andT_(max) were determined for each subject. The bioavailability ofsemaglutide via ID administration (Group 1) in comparison to the IV(Group 2) and SC (Group 3) administrations was determined.

Results

The results of the study are shown in Table 50 and in FIGS. 72A-72C showthe semaglutide concentration in blood over time after: IDadministration via the endoscopically placed ingestible device (FIG.72A); IV administration (FIG. 72B); and SC administration (FIG. 72C).

The bioavailability of semaglutide via ID administration was determinedrelative to IV or SC administration. The results are shown in Table 50.

TABLE 50 Semaglutide plasma PK in swine Route ID IV SC N 4 ^(a) 3 3T_(max) (hr) 6.67 ± 0.54    1.00 ± 0.00 18.67 ± 4.53 C_(max) (ng) 33.57± 19.04   279.00 ± 9.67 98.47 ± 3.49 (AUC)_(T0-T240 h) 1709.4 ± 1108.05 11371.67 ± 143.81 9695.00 ± 313.95 ng · hr/mL ± SEM Corrected 1789.42 ±1156.76 ^(a) N/A N/A (AUC)_(T0-T240 h) ng · hr/mL ± SEM Bioavailability15.74 ± 10.17 ^(a) 100% 85.26 ± 2.96 relative to IV ± SEMBioavailability 18.46 ± 11.95 ^(a) Not calculated 100% relative to SC ±SEM ^(a) AUC corrected for dose was used to calculate bioavailability.

Example 12—Evaluation of the Bioavailability of Adalimumab afterIntraduodenal Administration Via Endoscopic Needle Injection in FemaleYorkshire Pigs

Two studies were conducted to evaluate the plasma pharmacokinetics ofadalimumab in female Yorkshire pigs after intraduodenal (ID)administration via an endoscopic injection needle. The results werecompared with those obtained after administration of adalimumab via a2-nozzle jet delivery device, SC or IV (Example 5).

Test Article

Adalimumab in an aqueous buffer having an adalimumab concentration ofabout 100 mg/mL.

In Vivo Study Design

A total of 5 healthy female Yorkshire pigs (Sus scrofa domesticus)having a body weight of ˜25-40 kg were used in these studies, 3 in afirst study and 2 in a second study. Each animal received test articlevia intraduodenal (ID) administration via an injection needle. The studydesign is shown below in Table 51.

TABLE 51 Blood Dose Dose Dose Collection Study Route N Dose Conc. volumeTime Points 1 ID 3 40 mg 100 mg/mL 400 Pre-dose, 1, 3, 6, 8, 24, 72,(endoscopic microliters 144, and 240 hours post dose injection needle) 2ID 2 40 mg 100 mg/mL 400 Pre-dose, 1, 3, 6, 8, 24, 72, (endoscopicmicroliters 144, and 240 hours post dose injection needle)

Animals were housed one per cage and fasted for a minimum of 12 hoursprior to dosing. Food was returned at 4 hours post-dose. Water wassupplied ad libitum.

Intraduodenal (ID) administration was performed as follows. Theendoscope (Olympus OSF-V60 attached to an Olympus CV60 Tower) configuredwith an endoscopic injection needle was maneuvered into the pyloricsphincter with camera visualization to identify the third(inferior/horizontal) part of the duodenum (D3). Following confirmationof placement of the endoscopic injection needle in the correct region,the endoscope was retracted out of the pyloric sphincter, leaving theinjection device in the D3 region of the duodenum. Once it was confirmedthat the endoscopic injection needle was placed in the correct region,approximately 0.5 mL of saline was injected within the lamina propria ofthe mucosa to create a small bleb in the mucosa. The formulation wasthen injected into the bleb and flushed with approximately 0.8 mL ofsaline. The animals were kept under anesthesia through the 1 hour bloodcollection time point. All other blood collections were performed on thepigs without the use of anesthesia.

Sampling

Each blood sample was collected from the pig jugular vein, or othersuitable vessel via direct venipuncture, placed into a chilled tubecontaining K2-EDTA as the anticoagulant, and inverted several times tomix. Blood samples were kept on wet ice until centrifugation. Bloodsamples were centrifuged at a temperature of 4° C., at 3,000×g, for 5minutes and chilled throughout processing. Plasma was collected intopre-labeled polypropylene tubes and placed in a freezer set to maintain−60 to −80° C. prior to analysis.

Plasma samples were collected at pre-dose, 1, 3, 6, 8, 24, 72, 144, and240 hours post-dose in all animals and sent to an off-site laboratoryfor bioanalytical analysis. Samples were processed and analyzed by usingan adalimumab (anti-TNF-alpha) ELISA kit from Alpha Diagnostics, Inc.(Catalog #200 310-AHG). All plasma samples were diluted by 1:100dilution. Diluted samples were processed in duplicates and the meanOptical Density (O.D.) was measured using a SpectraMax plate reader andutilizing SoftMax Pro software for analysis. The Lower Limit ofQuantification (LLOQ) was calculated by adding 10× the standarddeviation value of the blanks O.D. to the average of the blank standardO.D. values. Mean concentrations of adalimumab were back interpolated toa 4-parameter log fit standard curve and subsequently multiplied by thedilution factor to obtain a final corrected adalimumab concentration.All data and pharmacokinetic parameters were analyzed and graphed byusing GraphPad Prism version 7.00 for Windows, GraphPad Software, LaJolla Calif. USA, www.graphpad.com (GraphPad Prism 7). The area underthe concentration curve (AUC) was calculated with the trapezoidal rules.

Results

PK analysis showed that one animal from the first study and one animalfrom the second study had quantifiable levels of adalimumab in plasma.The mean (AUC)_(T0-T240 h) for these two animals was determined and theresults are shown in FIG. 73 in comparison with subset of data fromExample 5, specifically, Example 5 Group 3 (ID administration viaingestible jet delivery device having an internal pressure of 320 psig),Group 4 (SC) and Group 5 (IV).

Example 13—Workflow for Clinical Trial

The following workflow can be used in clinical trials testing theingestible device 100 described above:

1. Capsule is pre-assembled with a target dispensing locationidentified.

2. Subject is briefed on device functionality and provides informedconsent.

3. Capsule is pre-loaded with a quantified amount of therapeutic drug.

4. Capsule is pressurized (drive mechanism).

5. Capsule is shipped to the clinical site.

6. Subject arrives at clinical site fasted.

7. Site personnel ensures that subject swallows the capsule undermedical supervision.

8. Capsule completes delivery of drug at pre-determined dispensinglocation.

9. Capsule naturally passes through GI tract and is excreted.

Other Embodiments

While certain embodiments have been provided, other embodiments arepossible.

As an example, some embodiments have been described in which aningestible device includes one or more pins. However, the disclosure isnot limited in this sense. Rather, in such embodiments, any elementhaving the appropriate shape and size, as well as being made of theappropriate material(s), may be used instead of (or, in some cases, inaddition to) one or more of the pins.

As another example, while embodiments have been described in which thedispensable substance is released in a single stage. Other embodimentsare possible. In some embodiments, multi-stage (e.g., two stage, threestage, four stage) release of the dispensable substance is used.Multi-staged release can be achieved, for example, via multiple elements(e.g., pins, plugs or the like) formed of different materials (e.g.,different enteric materials) that degrade/dissolve erode under differentconditions (e.g., different pH, temperature, enzyme concentration)present in different locations in the GI tract of a subject.

As an additional example, while embodiments have been described in whichan ingestible device includes a seal or a coating, the disclosure is notlimited in this sense. For example, in some embodiments, an ingestibledevice housing may be covered in one or more coverings, e.g., to sealthe ingestible device and/or to hold two modules of the device together.In certain embodiments, an ingestible device may be sealed to preventcontaminants from entering the ingestible device prior to administrationto a subject (e.g., during storage of the device) or afteradministration to a subject (e.g., during transit through the stomach),or to prevent the contents of the ingestible device (e.g., a dispensablesubstance) from exiting the ingestible device before desired (e.g.,prior to triggering). In certain embodiments, an ingestible device isassembled from two modules: one module contains the dispensablesubstance (“drug module”), while the other module contains the driveforce generator and the drive coupling (“drive module”). One or morecoverings can be used to partially or wholly join and/or seal the twomodules after they are assembled together to form an ingestible device.In some embodiments, one or more coverings cover the entirety of thehousing of the ingestible device, while in other embodiments one or morecoverings cover only a portion of the housing the ingestible device(e.g., parts of the housing with an opening, parts of the housing thatcomprise enteric materials, or parts of the housing assembled from twoor more different modules after the modules are joined together to forman ingestible device). Examples of covering materials include foils,films, and other materials that degrade or erode in the GI tract, and/orthat are made of a relatively low mechanical strength material (e.g., sothat a dispensable substance can pass through the covering and exit inthe form of a jet after triggering). In some embodiments, one or morecoverings are made of a gelatin material, for example, using agel-enrobed technology such as Press-Fit® or XPress-Fit® gelcap fromLonza (see, e.g., U.S. Pat. Nos. 5,317,849, 5,460,824, 5,464,631,5,511,361, 5,795,588, 5,609,010, 6,080,426, and 6,245,350). In someembodiments, the one or more coverings are applied to the device housingusing a cold-shrink process. In some embodiments, the one or morecoverings degrade or erode in the stomach or in the proximal smallintestine (e.g., in the duodenum).

As a further example, while certain embodiments of an ingestible devicehave been described in relation to certain forms of delivery(trans-epithelial, epithelial, topical), the disclosure is not limitedin this sense. As an example, in some embodiments, a device describedfor use in trans-epithelial delivery or for use in epithelial deliverycan be used in topical delivery. Generally, such embodiments involvemodifying the relevant parameters (e.g., internal pressure, fluidpressure) accordingly. As another example, in some embodiments, a devicedescribed for use in epithelial delivery or for use in epithelialdelivery can be used in topical delivery. Generally, such embodimentsinvolve modifying the relevant parameters (e.g., internal pressure,fluid pressure) accordingly.

As an additional example, in some embodiments, the volume of thepharmaceutical formulation deposited in the submucosa and/or the mucosa(e.g., into the lamina propria) is about 1 microliter to about 800microliters, about 10 microliters to about 800 microliters, about 50microliters to about 800 microliters, about 100 microliters to about 800microliters, about 200 microliters to about 800 microliters, about 300microliters to about 800 microliters, about 400 microliters to about 800microliters, about 500 microliters to about 800 microliters, about 600microliters to about 800 microliters, about 700 microliters to about 800microliters, about 1 microliter to about 700 microliters, about 10microliters to about 700 microliters, about 50 microliters to about 700microliters, about 100 microliters to about 700 microliters, about 200microliters to about 700 microliters, about 300 microliters to about 700microliters, about 400 microliters to about 700 microliters, about 400microliters to about 700 microliters, about 500 microliters to about 700microliters, about 600 microliters to about 700 microliters, about 1microliter to about 600 microliters, about 10 microliters to about 600microliters, about 50 microliters to about 600 microliters, about 100microliters to about 600 microliters, about 200 microliters to about 600microliters, about 300 microliters to about 600 microliters, about 400microliters to about 600 microliters, about 400 microliters to about 600microliters, about 500 microliters to about 600 microliters, about 1microliter to about 500 microliters, about 10 microliters to about 500microliters, about 50 microliters to about 500 microliters, about 100microliters to about 500 microliters, about 200 microliters to about 500microliters, about 300 microliters to about 500 microliters, about 400microliters to about 500 microliters, about 1 microliter to about 400microliters, about 10 microliters to about 400 microliters, about 50microliters to about 400 microliters, about 100 microliters to about 400microliters, about 200 microliters to about 400 microliters, or about300 microliters to about 400 microliters. In some embodiments, thevolume of the pharmaceutical formulation deposited in the submucosaand/or the mucosa (e.g., into the lamina propria) is about 1 microliterto about 500 microliters, about 10 microliters to about 400 microliters,about 50 microliters to about 400 microliters, about 100 microliters toabout 400 microliters, about 200 microliters to about 400 microliters,250 microliters to about 400 microliters, or about 300 microliters toabout 400 microliters. In some embodiments, the volume represents thetotal volume delivered by the one or more jets. In some embodiments, thevolume represents the total volume delivered (or released from theingestible device) via one jet, by two jets, by three jets, by fourjets, or by five jets. In some embodiments, the volume represents thetotal volume of the pharmaceutical formulation delivered by two jets.For example, when the volume of the pharmaceutical formulation is about400 microliters, and when the device has two nozzles, the volume ofpharmaceutical formulation delivered by each jet is about 200microliters.

As a further example, in some embodiments, the formulation is depositedin the submucosa and/or the mucosa (e.g., into the lamina propria) ofthe small intestine of the subject. In some embodiments, the formulationis deposited in the submucosa and/or the mucosa (e.g., into the laminapropria) of the duodenum of the subject. In some embodiments, theformulation is deposited in the submucosa and/or the mucosa (e.g., intothe lamina propria) of the jejunum of the subject. In some embodiments,the formulation is deposited in the submucosa and/or the mucosa (e.g.,into the lamina propria) of the ileum of the subject.

As another example, in some embodiments, the volume of thepharmaceutical formulation deposited in the mucosa is about 1 microliterto about 800 microliters, about 10 microliters to about 800 microliters,about 50 microliters to about 800 microliters, about 100 microliters toabout 800 microliters, about 200 microliters to about 800 microliters,about 300 microliters to about 800 microliters, about 400 microliters toabout 800 microliters, about 500 microliters to about 800 microliters,about 600 microliters to about 800 microliters, about 700 microliters toabout 800 microliters, about 1 microliter to about 700 microliters,about 10 microliters to about 700 microliters, about 50 microliters toabout 700 microliters, about 100 microliters to about 700 microliters,about 200 microliters to about 700 microliters, about 300 microliters toabout 700 microliters, about 400 microliters to about 700 microliters,about 400 microliters to about 700 microliters, about 500 microliters toabout 700 microliters, about 600 microliters to about 700 microliters,about 1 microliter to about 600 microliters, about 10 microliters toabout 600 microliters, about 50 microliters to about 600 microliters,about 100 microliters to about 600 microliters, about 200 microliters toabout 600 microliters, about 300 microliters to about 600 microliters,about 400 microliters to about 600 microliters, about 400 microliters toabout 600 microliters, about 500 microliters to about 600 microliters,about 1 microliter to about 500 microliters, about 10 microliters toabout 500 microliters, about 50 microliters to about 500 microliters,about 100 microliters to about 500 microliters, about 200 microliters toabout 500 microliters, about 300 microliters to about 500 microliters,about 400 microliters to about 500 microliters, about 1 microliter toabout 400 microliters, about 10 microliters to about 400 microliters,about 50 microliters to about 400 microliters, about 100 microliters toabout 400 microliters, about 200 microliters to about 400 microliters,or about 300 microliters to about 400 microliters. In some embodiments,the volume of the pharmaceutical formulation deposited in the mucosa isabout 1 microliter to about 500 microliters, about 10 microliters toabout 400 microliters, about 50 microliters to about 400 microliters,about 100 microliters to about 400 microliters, about 200 microliters toabout 400 microliters, 250 microliters to about 400 microliters, orabout 300 microliters to about 400 microliters. In some embodiments, thevolume represents the total volume delivered by the one or more jets. Insome embodiments, the volume represents the total volume delivered (orreleased from the ingestible device) via one jet, by two jets, by threejets, by four jets, or by five jets. In some embodiments, the volumerepresents the total volume of the pharmaceutical formulation deliveredby two jets. For example, when the volume of the pharmaceuticalformulation is about 400 microliters, and when the device has twonozzles, the volume of pharmaceutical formulation delivered by each jetis about 200 microliters.

As yet another example, in some embodiments, the volume of thepharmaceutical formulation deposited in the mucus is about 1 microliterto about 800 microliters, about 10 microliters to about 800 microliters,about 50 microliters to about 800 microliters, about 100 microliters toabout 800 microliters, about 200 microliters to about 800 microliters,about 300 microliters to about 800 microliters, about 400 microliters toabout 800 microliters, about 500 microliters to about 800 microliters,about 600 microliters to about 800 microliters, about 700 microliters toabout 800 microliters, about 1 microliter to about 700 microliters,about 10 microliters to about 700 microliters, about 50 microliters toabout 700 microliters, about 100 microliters to about 700 microliters,about 200 microliters to about 700 microliters, about 300 microliters toabout 700 microliters, about 400 microliters to about 700 microliters,about 400 microliters to about 700 microliters, about 500 microliters toabout 700 microliters, about 600 microliters to about 700 microliters,about 1 microliter to about 600 microliters, about 10 microliters toabout 600 microliters, about 50 microliters to about 600 microliters,about 100 microliters to about 600 microliters, about 200 microliters toabout 600 microliters, about 300 microliters to about 600 microliters,about 400 microliters to about 600 microliters, about 400 microliters toabout 600 microliters, about 500 microliters to about 600 microliters,about 1 microliter to about 500 microliters, about 10 microliters toabout 500 microliters, about 50 microliters to about 500 microliters,about 100 microliters to about 500 microliters, about 200 microliters toabout 500 microliters, about 300 microliters to about 500 microliters,about 400 microliters to about 500 microliters, about 1 microliter toabout 400 microliters, about 10 microliters to about 400 microliters,about 50 microliters to about 400 microliters, about 100 microliters toabout 400 microliters, about 200 microliters to about 400 microliters,or about 300 microliters to about 400 microliters. In some embodiments,the volume of the pharmaceutical formulation deposited in the mucus isabout 1 microliter to about 500 microliters, about 10 microliters toabout 400 microliters, about 50 microliters to about 400 microliters,about 100 microliters to about 400 microliters, about 200 microliters toabout 400 microliters, 250 microliters to about 400 microliters, orabout 300 microliters to about 400 microliters. In some embodiments, thevolume represents the total volume delivered by the one or more jets. Insome embodiments, the volume represents the total volume delivered (orreleased from the ingestible device) via one jet, by two jets, by threejets, by four jets, or by five jets. In some embodiments, the volumerepresents the total volume of the pharmaceutical formulation deliveredby two jets. For example, when the volume of the pharmaceuticalformulation is about 400 microliters, and when the device has twonozzles, the volume of pharmaceutical formulation delivered by each jetis about 200 microliters.

As a further example, in some embodiments, the volume of thepharmaceutical formulation released from the device is about 1microliter to about 800 microliters, about 10 microliters to about 800microliters, about 50 microliters to about 800 microliters, about 100microliters to about 800 microliters, about 200 microliters to about 800microliters, about 300 microliters to about 800 microliters, about 400microliters to about 800 microliters, about 500 microliters to about 800microliters, about 600 microliters to about 800 microliters, about 700microliters to about 800 microliters, about 1 microliter to about 700microliters, about 10 microliters to about 700 microliters, about 50microliters to about 700 microliters, about 100 microliters to about 700microliters, about 200 microliters to about 700 microliters, about 300microliters to about 700 microliters, about 400 microliters to about 700microliters, about 400 microliters to about 700 microliters, about 500microliters to about 700 microliters, about 600 microliters to about 700microliters, about 1 microliter to about 600 microliters, about 10microliters to about 600 microliters, about 50 microliters to about 600microliters, about 100 microliters to about 600 microliters, about 200microliters to about 600 microliters, about 300 microliters to about 600microliters, about 400 microliters to about 600 microliters, about 400microliters to about 600 microliters, about 500 microliters to about 600microliters, about 1 microliter to about 500 microliters, about 10microliters to about 500 microliters, about 50 microliters to about 500microliters, about 100 microliters to about 500 microliters, about 200microliters to about 500 microliters, about 300 microliters to about 500microliters, about 400 microliters to about 500 microliters, about 100microliters to about 450 microliters, about 225 microliters to about 450microliters, about 1 microliter to about 400 microliters, about 10microliters to about 400 microliters, about 50 microliters to about 400microliters, about 100 microliters to about 400 microliters, about 200microliters to about 400 microliters, about 250 microliters to about 400microliters, or about 300 microliters to about 400 microliters. In someembodiments, the total volume of the pharmaceutical formulation releasedfrom the device is about 1 microliter to about 500 microliters, about 10microliters to about 400 microliters, about 50 microliters to about 400microliters, about 100 microliters to about 400 microliters, about 200microliters to about 400 microliters, 250 microliters to about 400microliters, or about 300 microliters to about 400 microliters. In someembodiments, the volume represents the total volume delivered by the oneor more jets. In some embodiments, the volume represents the totalvolume delivered (or released from the ingestible device) via one jet,by two jets, by three jets, by four jets, or by five jets. In someembodiments, the volume represents the total volume of thepharmaceutical formulation delivered by two jets. For example, when thevolume of the pharmaceutical formulation is about 400 microliters, andwhen the device has two nozzles, the volume of pharmaceuticalformulation delivered by each jet can be about 200 microliters.

As another example, in some embodiments, the volume of thepharmaceutical formulation topically delivered to the gastrointestinaltract of the subject is about 1 microliter to about 800 microliters,about 10 microliters to about 800 microliters, about 50 microliters toabout 800 microliters, about 100 microliters to about 800 microliters,about 200 microliters to about 800 microliters, about 300 microliters toabout 800 microliters, about 400 microliters to about 800 microliters,about 500 microliters to about 800 microliters, about 600 microliters toabout 800 microliters, about 700 microliters to about 800 microliters,about 1 microliter to about 700 microliters, about 10 microliters toabout 700 microliters, about 50 microliters to about 700 microliters,about 100 microliters to about 700 microliters, about 200 microliters toabout 700 microliters, about 300 microliters to about 700 microliters,about 400 microliters to about 700 microliters, about 400 microliters toabout 700 microliters, about 500 microliters to about 700 microliters,about 600 microliters to about 700 microliters, about 1 microliter toabout 600 microliters, about 10 microliters to about 600 microliters,about 50 microliters to about 600 microliters, about 100 microliters toabout 600 microliters, about 200 microliters to about 600 microliters,about 300 microliters to about 600 microliters, about 400 microliters toabout 600 microliters, about 400 microliters to about 600 microliters,about 500 microliters to about 600 microliters, about 1 microliter toabout 500 microliters, about 10 microliters to about 500 microliters,about 50 microliters to about 500 microliters, about 100 microliters toabout 500 microliters, about 200 microliters to about 500 microliters,about 300 microliters to about 500 microliters, about 400 microliters toabout 500 microliters, about 1 microliter to about 400 microliters,about 10 microliters to about 400 microliters, about 50 microliters toabout 400 microliters, about 100 microliters to about 400 microliters,about 200 microliters to about 400 microliters, or about 300 microlitersto about 400 microliters. In some embodiments, the volume of thepharmaceutical formulation topically delivered to the gastrointestinaltract of the subject is about 1 microliter to about 500 microliters,about 10 microliters to about 400 microliters, about 50 microliters toabout 400 microliters, about 100 microliters to about 400 microliters,about 200 microliters to about 400 microliters, 250 microliters to about400 microliters, or about 300 microliters to about 400 microliters. Insome embodiments, the volume represents the total volume delivered bythe one or more jets. In some embodiments, the volume represents thetotal volume delivered (or released from the ingestible device) via onejet, by two jets, by three jets, by four jets, or by five jets. In someembodiments, the volume represents the total volume of thepharmaceutical formulation delivered by two jets. For example, when thevolume of the pharmaceutical formulation is about 400 microliters, andwhen the device has two nozzles, the volume of pharmaceuticalformulation delivered by each jet can be about 200 microliters.

As yet another example, in some embodiments, a first portion of thepharmaceutical formulation released from the device is deposited in thesubmucosa and a second portion is deposited in the mucosa (such as thelamina propria), and/or is released into the lumen, and may subsequentlyadhere to the mucus of the gastrointestinal tract. In some embodiments,the first portion of the pharmaceutical formulation deposited into thesubmucosa contains at least about 99% of the total pharmaceuticalformulation released from the device, wherein the % is a w/w %, a w/v %,or a v/v % of the pharmaceutical formulation. In other embodiments, thefirst portion of the pharmaceutical formulation deposited into thesubmucosa contains at least about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 75%, about 70%, about 65%, about 60%, about55% or about 50% of the pharmaceutical formulation, wherein the % is aw/w %, a w/v %, or a v/v % of the pharmaceutical formulation. In yetother embodiments, the first portion of the pharmaceutical formulationdeposited into the submucosa contains at least about 45%, at least about40%, at least about 35%, at least about 30%, at least about 25%, atleast about 20%, at least about 15%, at least about 10%, or at leastabout 5% of the pharmaceutical formulation, wherein the % is a w/w %, aw/v %, or a v/v % of the pharmaceutical formulation.

As an additional example, in some embodiments, the formulation istopically delivered to the small intestine of the subject. In someembodiments, the formulation is topically delivered to the duodenum ofthe subject. In some embodiments, the formulation is topically deliveredto the jejunum of the subject. In some embodiments, the formulation istopically delivered to the ileum of the subject. In some embodiments,the topical delivery of the formulation to the small intestine of thesubject is for use in treating ileal Crohn's disease.

As another example, in some embodiments, the formulation is topicallydelivered to the large intestine of the subject. In some embodiments,the formulation is topically delivered to the cecum of the subject. Insome embodiments, the formulation is topically delivered to the colon ofthe subject. In some embodiments, the formulation is topically deliveredto the rectum of the subject. In some embodiments, the topical deliveryof the formulation to the large intestine of the subject is for use intreating an inflammatory bowel disease (IBD), where the IBD is Crohn'sdisease or ulcerative colitis.

As a further example, in some embodiments of any of the devices ormethods described herein, the releasing of the therapeutic is triggeredby one or more of: a pH in the jejunum of about 6.1 to about 7.2, a pHin the mid small bowel of about 7.0 to about 7.8, a pH in the ileum ofabout 7.0 to about 8.0, a pH in the right colon of about 5.7 to about7.0, a pH in the mid colon of about 5.7 to about 7.4, or a pH in theleft colon of about 6.3 to about 7.7, such as about 7.0.

As another example, in some embodiments of any of the devices or methodsdescribed herein, the releasing of the therapeutic is triggered bydegradation of a release component located in the device. In someembodiments of any of the devices or methods described herein, thereleasing of the therapeutic is dependent on enzymatic activity at or inthe vicinity of the location. In some embodiments of any of the devicesor methods described herein, the composition includes a plurality ofelectrodes including a coating, and releasing the therapeutic istriggered by an electric signal by the electrodes resulting from theinteraction of the coating with an intended site of release of thetherapeutic. In some embodiments of any of the devices or methodsdescribed herein, the release of the therapeutic is triggered by aremote electromagnetic signal. In some embodiments of any of the devicesor methods described herein, the release of the therapeutic is triggeredby generation in the composition of a gas in an amount sufficient toexpel the therapeutic. In some embodiments of any of the devices ormethods described herein, the release of the therapeutic is triggered byan electromagnetic signal generated within the device according to apre-determined drug release profile.

As another example, in some embodiments, the peak fluid pressure or theinternal pressure on the pharmaceutical formulation inside the device,prior to release from the device, is at least about 100 psig, optionallyranging from about 100 psig to about 500 psig, and the mean jet velocityof each of the one or more jets upon release of the pharmaceuticalformulation from the device ranges from about 10 m/s to about 50 m/s. Ina further embodiment, the total volume of the pharmaceutical formulationreleased from the device ranges from about 50 microliters to about 500microliters, from about 100 microliters to about 450 microliters, fromabout 200 microliters to about 400 microliters, from 250 microliters toabout 400 microliters, or from about 300 microliters to about 400microliters. In yet a further embodiment, the device comprises 1 to 5nozzles, 2 to 4 nozzles, or 2 nozzles, wherein each nozzle has an innerdiameter at the point of exit from the device ranging from about 0.1 mmto about 0.75 mm, or from about 0.30 mm to about 0.50 mm. In someembodiments, the mean jet impact pressure applied by each of the one ormore jets at the target surface ranges from about 7.25 psig to 145 psig.

As yet another example, in some embodiments, the peak fluid pressure orthe internal pressure on the pharmaceutical formulation inside thedevice, prior to release from the device, is at least about 100 psig,optionally ranging from about 100 psig to about 450 psig, the mean jetvelocity of each of the one or more jets upon release of thepharmaceutical formulation from the device ranges from about 10 m/s toabout 50 m/s, the total volume of the pharmaceutical formulationreleased from the device ranges from about 200 microliters to about 500microliters, from about 225 microliters to about 450 microliters, orfrom about 250 to about 400 microliters. In yet a further embodiment,the device comprises 2, 3 or 4 nozzles, in some preferred embodiments, 2nozzles, wherein each nozzle has an inner diameter at the point of exitfrom the device ranging from about 0.2 mm to about 0.6 mm, or from about0.30 mm to about 0.50 mm, for example, 0.35 mm. In some embodiments, themean jet impact pressure applied by each of the one or more jets at thetarget surface ranges from about 7.25 psig to 145 psig.

In a further example, in some embodiments, the peak fluid pressure orthe internal pressure on the pharmaceutical formulation inside thedevice, prior to release from the device is at least about 150 psig,optionally ranging from about 150 psig to about 400 psig, and the peakmean jet velocity of each of the one or more jets upon release of thepharmaceutical formulation from the device ranges from about 15 m/s toabout 40 m/s, or from about 18 m/s to about 35 m/s. In a furtherembodiment, the total volume of the pharmaceutical formulation releasedfrom the device ranges from about 50 microliters to about 500microliters, from about 100 microliters to about 450 microliters, fromabout 200 microliters to about 400 microliters, from 250 microliters toabout 400 microliters, or from about 300 microliters to about 400microliters. In yet a further embodiment, the device comprises 1 to 5nozzles, 2 to 4 nozzles, or 2 nozzles, wherein each nozzle has an innerdiameter at the point of exit from the device ranging from about 0.1 mmto about 0.75 mm, or from about 0.30 mm to about 0.50 mm, for example,about 0.35 mm. In some embodiments, the mean jet impact pressure appliedby each of the one or more jets at the target surface ranges from about21.76 psig to about 72.52 psig, or from about 29 psig to about 65.37psig.

In still a further example, in some embodiments, the peak fluid pressureor the internal pressure on the pharmaceutical formulation inside thedevice, prior to release from the device is at least about 150 psig,optionally ranging from about 150 psig to about 350 psig, and the meanvelocity of each of the one or more jets upon release of thepharmaceutical formulation from the device ranges from about 18 m/s toabout 35 m/s, or from about 20 m/s to about 30 m/s. In a furtherembodiment, the total volume of the pharmaceutical formulation releasedfrom the device ranges from about 200 microliters to about 500microliters, from about 225 microliters to about 450 microliters, orfrom about 250 to about 400 microliters. In yet a further embodiment,the device comprises 2, 3 or 4 nozzles, in some preferred embodiments, 2nozzles, wherein each nozzle has an inner diameter at the point of exitfrom the device ranging from about 0.2 mm to about 0.6 mm, or from about0.30 mm to about 0.50 mm, for example, 0.35 mm. In some embodiments, themean jet impact pressure applied by each of the one or more jets at thetarget surface ranges from about 21.76 psig to about 72.52 psig, or fromabout 29 psig to about 65.37 psig.

In another example, in some embodiments, the peak fluid pressure or theinternal pressure on the pharmaceutical formulation inside the device,prior to release from the device is at least about 200 psig, optionallyranging from about 200 psig to about 400 psig, and the mean jet velocityof each of the one or more jets upon release of the pharmaceuticalformulation from the device ranges from about 23 m/s to about 36 m/s, orfrom about 25 m/s to about 35 m/s. In a further embodiment, the totalvolume of the pharmaceutical formulation released from the device rangesfrom about 50 microliters to about 500 microliters, from about 100microliters to about 450 microliters, from about 200 microliters toabout 400 microliters, from 250 microliters to about 400 microliters, orfrom about 300 microliters to about 400 microliters. In yet a furtherembodiment, the device comprises 1 to 5 nozzles, 2 to 4 nozzles, or 2nozzles, wherein each nozzle has an inner diameter at the point of exitfrom the device ranging from about 0.1 mm to about 0.75 mm, or fromabout 0.30 mm to about 0.50 mm, for example, about 0.35 mm. In someembodiments, the mean jet impact pressure applied by each of the one ormore jets at the target surface ranges from about 29 psig to about 72.52psig, from about 36.26 psig to about 72.52 psig, from about 43.51 psigto about 72.52 psig, or from about 26.26 psig to about 65.27 psig.

In still another example, in some embodiments, the peak fluid pressureor the internal pressure on the pharmaceutical formulation inside thedevice, prior to release from the device is at least about 220 psig, orat least about 225 psig, optionally ranging from about 225 psig to about400 psig, and the mean jet velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device ranges fromabout 24 m/s to about 36 m/s, or from about 25 m/s to about 35 m/s. In afurther embodiment, the total volume of the pharmaceutical formulationreleased from the device ranges from about 200 microliters to about 500microliters, from about 225 microliters to about 450 microliters, orfrom about 250 to about 400 microliters. In yet a further embodiment,the device comprises 2, 3 or 4 nozzles, in some preferred embodiments, 2nozzles, wherein each nozzle has an inner diameter at the point of exitfrom the device ranging from about 0.2 mm to about 0.6 mm, or from about0.30 mm to about 0.50 mm, for example, 0.35 mm. In some embodiments, themean jet impact pressure applied by each of the one or more jets at thetarget surface ranges from about 29 psig to about 72.52 psig, from about36.26 psig to about 72.52 psig, from about 43.51 psig to about 72.52psig, or from about 26.26 psig to about 65.27 psig.

In a further example, in some embodiments, the peak fluid pressure orthe internal pressure on the pharmaceutical formulation inside thedevice, prior to release from the device is at least about 225 psig, orat least about 250 psig, optionally ranging from about 250 psig to about400 psig, and the mean jet velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device ranges fromabout 25 m/s to about 36 m/s, or from about 25 m/s to about 35 m/s. In afurther embodiment, the total volume of the pharmaceutical formulationreleased from the device ranges from about 50 microliters to about 500microliters, from about 100 microliters to about 450 microliters, fromabout 200 microliters to about 400 microliters, from 250 microliters toabout 400 microliters, or from about 300 microliters to about 400microliters. In yet a further embodiment, the device comprises 1 to 5nozzles, 2 to 4 nozzles, or 2 nozzles, wherein each nozzle has an innerdiameter at the point of exit from the device ranging from about 0.1 mmto about 0.75 mm, or from about 0.30 mm to about 0.50 mm, for example,about 0.35 mm. In some embodiments, the mean jet impact pressure appliedby each of the one or more jets at the target surface ranges from about29 psig to about 72.52 psig, from about 36.26 psig to about 72.52 psig,from about 43.51 psig to about 72.52 psig, or from about 26.26 psig toabout 65.27 psig.

In another example, in some embodiments, the peak fluid pressure or theinternal pressure on the pharmaceutical formulation inside the device,prior to release from the device, is at least about 250 psig, or atleast about 275 psig, optionally ranging from about 275 psig to about375 psig, and the mean jet velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device ranges fromabout 25 m/s to about 35 m/s, or from about 25 m/s to about 30 m/s. In afurther embodiment, the total volume of the pharmaceutical formulationreleased from the device ranges from about 200 microliters to about 500microliters, from about 225 microliters to about 450 microliters, orfrom about 250 to about 400 microliters. In yet a further embodiment,the device comprises 2, 3 or 4 nozzles, in some preferred embodiments, 2nozzles, wherein each nozzle has an inner diameter at the point of exitfrom the device ranging from about 0.2 mm to about 0.6 mm, or from about0.30 mm to about 0.50 mm, for example, 0.35 mm. In some embodiments, themean impact pressure applied by each of the one or more jets at thetarget surface ranges from about 43.51 psig to about 72.52 psig, or fromabout 50.76 psig to about 65.27 psig.

In an additional example, in some embodiments, the peak fluid pressureor the internal pressure on the pharmaceutical formulation inside thedevice, prior to release from the device is at least about 275 psig, orat least about 300 psig, optionally ranging from about 300 psig to about375 psig, and the mean velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device ranges fromabout 25 m/s to about 35 m/s, or from about 25 m/s to about 30 m/s. In afurther embodiment, the total volume of the pharmaceutical formulationreleased from the device ranges from about 50 microliters to about 500microliters, from about 100 microliters to about 450 microliters, fromabout 200 microliters to about 400 microliters, from 250 microliters toabout 400 microliters, or from about 300 microliters to about 400microliters. In yet a further embodiment, the device comprises 1 to 5nozzles, 2 to 4 nozzles, or 2 nozzles, wherein each nozzle has an innerdiameter at the point of exit from the device ranging from about 0.1 mmto about 0.75 mm, or from about 0.30 mm to about 0.50 mm, for example,about 0.35 mm. In some embodiments, the mean impact pressure applied byeach of the one or more jets at the target surface ranges from about43.51 psig to about 72.52 psig, or from about 50.76 psig to about 65.27psig.

In yet a further example, in some embodiments, the peak fluid pressureor the internal pressure on the pharmaceutical formulation inside thedevice, prior to release from the device, is at least about 300 psig, orat least about 320 psig, optionally ranging from about 320 psig to about375 psig, and the mean jet velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device ranges fromabout 26 m/s to about 35 m/s, from about 27 m/s to about 30 m/s, or fromabout 28 m/s to about 30 m/s. In a further embodiment, the total volumeof the pharmaceutical formulation released from the device ranges fromabout 200 microliters to about 500 microliters, from about 225microliters to about 450 microliters, or from about 250 to about 400microliters. In yet a further embodiment, the device comprises 2, 3 or 4nozzles, in some preferred embodiments, 2 nozzles, wherein each nozzlehas an inner diameter at the point of exit from the device ranging fromabout 0.2 mm to about 0.6 mm, or from about 0.30 mm to about 0.50 mm,for example, 0.35 mm. In some embodiments, the mean impact pressureapplied by each of the one or more jets at the target surface rangesfrom about 58.0 psig to about 72.52 psig, from about 59.47 psig to about68.17 psig, from about 60.92 psig to about 66.72 psig, from about 63.37psig to about 65.27 psig.

In another example, in some embodiments, there is provided a method ofdepositing a pharmaceutical formulation containing a small molecule drugto the submucosa and/or the mucosa of the small intestine of thesubject. In some embodiments, the small molecule has a molecular weightranging from about 50 Da to about 1500 Da, and the peak fluid pressureor the internal pressure of the pharmaceutical formulation, prior torelease from the device, is at least about 100 psig. In someembodiments, the internal pressure is at least about 150 psig. In someembodiments, the internal pressure is at least about 200 psig. In someembodiments, the internal pressure is at least about 220 psig. In someembodiments, the internal pressure ranges from about 150 psig to about450 psig, from about 150 psig to about 400 psig, from about 150 psig toabout 375 psig, from about 150 psig to about 350 psig, from about 150 toabout 325 psig, or from about 150 to about 300 psig. In otherembodiments, the internal pressure for delivering the small moleculedrug ranges from about 175 psig to about 450 psig, from about 175 psigto about 400 psig, from about 175 psig to about 375 psig, from about 175psig to about 350 psig, from about 175 to about 325 psig, or from about175 to about 300 psig. In other embodiments, the internal pressure fordelivering the small molecule drug ranges from about 200 psig to about450 psig, from about 200 psig to about 400 psig, from about 200 psig toabout 375 psig, from about 200 psig to about 350 psig, from about 200 toabout 325 psig, or from about 200 psig to about 300 psig. In otherembodiments, the internal pressure for delivering the small moleculedrug ranges from about 220 psig to about 450 psig, from about 220 psigto about 400 psig, from about 220 psig to about 375 psig, from about 220psig to about 350 psig, from about 220 psig to about 325 psig, or fromabout 220 psig to about 300 psig. In other embodiments, the internalpressure for delivering the small molecule drug ranges from about 225psig to about 450 psig, from about 225 psig to about 400 psig, fromabout 225 psig to about 375 psig, from about 225 psig to about 350 psig,from about 225 psig to about 325 psig, or from about 225 psig to about300 psig.

In yet another example, in some embodiments, there is provided a methodof depositing a pharmaceutical formulation containing a medium sizeddrug or peptide to the submucosa and/or the mucosa (e.g., into thelamina propria) of the small intestine of the subject. In someembodiments, the drug has a molecular weight is greater than about 1500Da and less than about 20 kDa, less than about 30 kDa, less than about40 kDa, less than about 50 kDa or less than about 60 kDa, and the peakfluid pressure or the internal pressure on the pharmaceuticalformulation, prior to release from the device, is at least about 150psig. In some embodiments, the internal pressure is at least about 200psig. In some embodiments, the internal pressure is at least about 220psig. In some embodiments, the internal pressure is at least about 225psig. In some embodiments, the internal pressure ranges from about 200psig to about 450 psig, about 200 psig to about 400 psig, from about 200psig to about 375 psig, from about 200 psig to about 350 psig, fromabout 200 to about 325 psig, or from about 200 to about 300 psig. Inother embodiments, the internal pressure ranges from about 220 psig toabout 450 psig, about 220 psig to about 400 psig, from about 220 psig toabout 375 psig, from about 220 psig to about 350 psig, from about 220psig to about 325 psig, or from about 220 psig to about 300 psig. Inother embodiments, the internal pressure ranges from about 225 psig toabout 450 psig, 225 psig to about 400 psig, from about 225 psig to about375 psig, from about 225 psig to about 350 psig, from about 225 psig toabout 325 psig, or from about 225 psig to about 300 psig. In otherembodiments, the internal pressure ranges from about 250 psig to about450 psig, 250 psig to about 400 psig, from about 250 psig to about 375psig, from about 250 psig to about 350 psig, from about 250 psig toabout 325 psig, or from about 250 psig to about 300 psig. In otherembodiments, the internal pressure ranges from about 275 psig to about450 psig, 275 psig to about 400 psig, from about 275 psig to about 375psig, from about 275 psig to about 350 psig, from about 275 psig toabout 325 psig, or from about 275 psig to about 300 psig. In otherembodiments, the internal pressure ranges from about 300 psig to about450 psig, from about 300 psig to about 400 psig, from about 300 psig toabout 375 psig, from about 300 psig to about 350 psig, or from about 300psig to about 325 psig.

In an additional example, in some embodiments, there is provided amethod of depositing a pharmaceutical formulation containing a largedrug, such a therapeutic protein or antibody, to the submucosa and/orthe mucosa (e.g., into the lamina propria) of the small intestine of thesubject. In some embodiments, the drug has a molecular weight is atleast about 20 kDa, at least about 30 kDa, at least about 40 kDa, atleast about 50 kDa or at least about 60 kDa. In some embodiments, thedrug has a molecular weight ranging from about 20 kDa to about 200 kDa,from about 20 kDa to about 175 kDa, or from about 20 kDa to about 150kDa. In some other embodiments, the drug has a molecular weight rangingfrom about 60 kDa to about 200 kDa, from about 60 kDa to about 175 kDa,or from about 60 kDa to about 150 kDa. In some embodiments, the peakfluid pressure or the internal pressure on the pharmaceuticalformulation, prior to release from the device, is at least about 225psig. In some embodiments, the internal pressure is at least about 230psig. In some embodiments, the internal pressure is at least about 235psig, at least about 240 psig, at least about 245 psig, or at leastabout 250 psig. In some embodiments, the internal pressure is at leastabout 275 psig, at least about 300 psig, or at least about 320 psig. Insome embodiments, the internal pressure ranges from about 225 psig toabout 500 psig, from about 225 psig to about 475 psig, from about 225psig to about 450 psig, from about 225 to about 425 psig, from about 225to about 400 psig, from about 225 to about 375 psig, from about 225 toabout 350 psig, or from about 225 to about 325 psig. In someembodiments, the internal pressure ranges from about 250 psig to about500 psig, from about 250 psig to about 475 psig from about 250 psig toabout 450 psig, from about 250 to about 425 psig, from about 250 toabout 400 psig, from about 250 to about 375 psig, from about 250 toabout 350 psig, or from about 250 to about 325 psig. In someembodiments, the internal pressure ranges from about 275 psig to about500 psig, from about 275 psig to about 475 psig, from about 275 psig toabout 450 psig, from about 275 to about 425 psig, from about 275 toabout 400 psig, from about 275 to about 375 psig, from about 275 toabout 350 psig, or from about 275 to about 325 psig. In someembodiments, the internal pressure ranges from about 300 psig to about500 psig, from about 300 psig to about 475 psig, from about 300 psig toabout 450 psig, from about 300 to about 425 psig, from about 300 toabout 400 psig, from about 300 to about 375 psig, from about 300 toabout 350 psig, or from about 300 to about 325 psig. In someembodiments, the internal pressure ranges from about 320 psig to about500 psig, from about 320 psig to about 475 psig, from about 320 psig toabout 450 psig, from about 320 to about 425 psig, from about 320 toabout 400 psig, from about 320 to about 375 psig, or from about 320 toabout 350 psig.

In some embodiments, the internal pressure on the pharmaceuticalformulation inside the device, prior to release from the device (i.e.,the peak fluid pressure), is at least about 100 psig, optionally ofabout 100 psig to about 450 psig. In a further embodiment, the meanvelocity of each of the one or more jets upon release of thepharmaceutical formulation from the device is about 10 m/s to about 50m/s. In yet a further embodiment, the total volume of the pharmaceuticalformulation released from the device is about 200 microliters to about500 microliters, about 225 microliters to about 450 microliters, orabout 250 to about 400 microliters. In yet a further embodiment, thedevice comprises 2, 3 or 4 nozzles, in some preferred embodiments, 2nozzles, wherein each nozzle has an inner diameter at the point of exitfrom the device of about 0.2 mm to about 0.6 mm, or about 0.30 mm toabout 0.50 mm, for example, 0.35 mm. In some embodiments, the impactpressure applied by each of the one or more jets at the target surfaceis about 0.05 MPa (7.25 psig) to about 1 MPa (145 psig).

In some embodiments, the internal pressure on the pharmaceuticalformulation inside the device, prior to release from the device (i.e.,the peak fluid pressure), is at least about 150 psig, optionally ofabout 150 psig to about 400 psig. In a further embodiment, the meanvelocity of each of the one or more jets upon release of thepharmaceutical formulation from the device is about 15 m/s to about 40m/s, or about 18 m/s to about 35 m/s. In a further embodiment, the totalvolume of the pharmaceutical formulation released from the device isabout 50 microliters to about 500 microliters, about 100 microliters toabout 450 microliters, about 200 microliters to about 400 microliters,250 microliters to about 400 microliters, or about 300 microliters toabout 400 microliters. In yet a further embodiment, the device comprises1 to 5 nozzles, 2 to 4 nozzles, or 2 nozzles, wherein each nozzle has aninner diameter at the point of exit from the device of about 0.1 mm toabout 0.75 mm, or about 0.30 mm to about 0.50 mm, for example, about0.35 mm. In some embodiments, the impact pressure applied by each of theone or more jets at the target surface is about 0.15 MPa (21.8 psig) toabout 0.5 MPa (72.5 psig), or about 0.2 MPa (29 psig) to about 0.45 MPa(65.3 psig).

In some embodiments, the internal pressure on the pharmaceuticalformulation inside the device, prior to release from the device (i.e.,the peak fluid pressure), is at least about 150 psig, optionally ofabout 150 psig to about 350 psig. In a further embodiment, the meanvelocity of each of the one or more jets upon release of thepharmaceutical formulation from the device is about 18 m/s to about 35m/s, or about 20 m/s to about 30 m/s. In yet a further embodiment, thetotal volume of the pharmaceutical formulation released from the deviceis about 200 microliters to about 500 microliters, about 225 microlitersto about 450 microliters, or about 250 to about 400 microliters. In yeta further embodiment, the device comprises 2, 3 or 4 nozzles, in somepreferred embodiments, 2 nozzles, wherein each nozzle has an innerdiameter at the point of exit from the device of about 0.2 mm to about0.6 mm, or about 0.30 mm to about 0.50 mm, for example, 0.35 mm. In someembodiments, the impact pressure applied by each of the one or more jetsat the target surface is about 00.15 MPa (21.8 psig) to about 0.5 MPa(72.5 psig), or about 0.2 MPa (29 psig) to about 0.45 MPa (65.3 psig).

In some embodiments, the internal pressure on the pharmaceuticalformulation inside the device, prior to release from the device (i.e.,the peak fluid pressure), is at least about 200 psig, optionally ofabout 200 psig to about 400 psig. In a further embodiment, the meanvelocity of each of the one or more jets upon release of thepharmaceutical formulation from the device is about 23 m/s to about 36m/s, or about 25 m/s to about 35 m/s. In yet a further embodiment, thetotal volume of the pharmaceutical formulation released from the deviceis about 50 microliters to about 500 microliters, about 100 microlitersto about 450 microliters, about 200 microliters to about 400microliters, 250 microliters to about 400 microliters, or about 300microliters to about 400 microliters. In yet a further embodiment, thedevice comprises 1 to 5 nozzles, 2 to 4 nozzles, or 2 nozzles, whereineach nozzle has an inner diameter at the point of exit from the deviceof about 0.1 mm to about 0.75 mm, or about 0.30 mm to about 0.50 mm, forexample, about 0.35 mm. In some embodiments, the impact pressure appliedby each of the one or more jets at the target surface is about 0.2 MPa(29 psig) to about 0.5 MPa (72.5 psig), about 0.25 (36.3 psig) to about0.5 MPa (72.5 psig), about 0.3 MPa (43.5 psig) to about 0.5 MPa (72.5psig), or about 0.25 (36.3 psig) to about 0.45 MPa (65.3 psig).

In some embodiments, the internal pressure on the pharmaceuticalformulation inside the device, prior to release from the device (i.e.,the peak fluid pressure), is at least about 220 psig, or at least about225 psig, optionally of about 225 psig to about 400 psig. In a furtherembodiment, the mean velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device is about 24m/s to about 36 m/s, or about 25 m/s to about 35 m/s. In a furtherembodiment, the total volume of the pharmaceutical formulation releasedfrom the device is about 200 microliters to about 500 microliters, about225 microliters to about 450 microliters, or about 250 to about 400microliters. In yet a further embodiment, the device comprises 2, 3 or 4nozzles, in some preferred embodiments, 2 nozzles, wherein each nozzlehas an inner diameter at the point of exit from the device of about 0.2mm to about 0.6 mm, or about 0.30 mm to about 0.50 mm, for example, 0.35mm. In some embodiments, the impact pressure applied by each of the oneor more jets at the target surface is about 0.25 (36.3 psig) to about0.5 MPa (72.5 psig), about 0.3 MPa (43.5 psig) to about 0.5 MPa (72.5psig), or about 0.25 (36.3 psig) to about 0.45 MPa (65.3 psig).

In some embodiments, the internal pressure on the pharmaceuticalformulation inside the device, prior to release from the device (i.e.,the peak fluid pressure), is at least about 225 psig, or at least about250 psig, optionally of about 250 psig to about 400 psig. In a furtherembodiment, the mean velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device is about 25m/s to about 36 m/s, or about 25 m/s to about 35 m/s. In yet a furtherembodiment, the total volume of the pharmaceutical formulation releasedfrom the device is about 50 microliters to about 500 microliters, about100 microliters to about 450 microliters, about 200 microliters to about400 microliters, 250 microliters to about 400 microliters, or about 300microliters to about 400 microliters. In yet a further embodiment, thedevice comprises 1 to 5 nozzles, 2 to 4 nozzles, or 2 nozzles, whereineach nozzle has an inner diameter at the point of exit from the deviceof about 0.1 mm to about 0.75 mm, or about 0.30 mm to about 0.50 mm, forexample, about 0.35 mm. In some embodiments, the impact pressure appliedby each of the one or more jets at the target surface is about 0.25(36.3 psig) to about 0.5 MPa (72.5 psig), about 0.3 MPa (43.5 psig) toabout 0.5 MPa (72.5 psig), or about 0.25 (36.3 psig) to about 0.45 MPa(65.3 psig).

In some embodiments, the internal pressure on the pharmaceuticalformulation inside the device, prior to release from the device (i.e.,the peak fluid pressure), is at least about 250 psig, or at least about275 psig, optionally of about 275 psig to about 375 psig. In a furtherembodiment, the mean velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device is about 25m/s to about 35 m/s, or about 25 m/s to about 30 m/s. In yet a furtherembodiment, the total volume of the pharmaceutical formulation releasedfrom the device is about 200 microliters to about 500 microliters, about225 microliters to about 450 microliters, or about 250 to about 400microliters. In yet a further embodiment, the device comprises 2, 3 or 4nozzles, in some preferred embodiments, 2 nozzles, wherein each nozzlehas an inner diameter at the point of exit from the device of about 0.2mm to about 0.6 mm, or about 0.30 mm to about 0.50 mm, for example, 0.35mm. In some embodiments, the impact pressure applied by each of the oneor more jets at the target surface is about about 0.3 MPa (43.5 psig) toabout 0.5 MPa (72.5 psig), or about 0.25 (36.3 psig) to about 0.45 MPa(65.3 psig).

In some embodiments, the internal pressure on the pharmaceuticalformulation inside the device, prior to release from the device (i.e.,the peak fluid pressure), is at least about 275 psig, or at least about300 psig, optionally of about 300 psig to about 375 psig. In a furtherembodiment, the mean velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device is about 25m/s to about 35 m/s, or about 25 m/s to about 30 m/s. In yet a furtherembodiment, the total volume of the pharmaceutical formulation releasedfrom the device is about 50 microliters to about 500 microliters, about100 microliters to about 450 microliters, about 200 microliters to about400 microliters, 250 microliters to about 400 microliters, or about 300microliters to about 400 microliters. In yet a further embodiment, thedevice comprises 1 to 5 nozzles, 2 to 4 nozzles, or 2 nozzles, whereineach nozzle has an inner diameter at the point of exit from the deviceof about 0.1 mm to about 0.75 mm, or about 0.30 mm to about 0.50 mm, forexample, about 0.35 mm. In some embodiments, the impact pressure appliedby each of the one or more jets at the target surface is about 0.35 MPa(50.8 psig) to about 0.5 MPa (72.5 psig), or about 0.4 (58 psig) toabout 0.45 MPa (65.3 psig).

In some embodiments, the internal pressure on the pharmaceuticalformulation inside the device, prior to release from the device (i.e.,the peak fluid pressure), is at least about 300 psig, or at least about320 psig, optionally of about 320 psig to about 375 psig. In a furtherembodiment, the mean velocity of each of the one or more jets uponrelease of the pharmaceutical formulation from the device is about 26m/s to about 35 m/s, about 27 m/s to about 30 m/s, or about 28 m/s toabout 30 m/s. In yet a further embodiment, the total volume of thepharmaceutical formulation released from the device is about 200microliters to about 500 microliters, about 225 microliters to about 450microliters, or about 250 to about 400 microliters. In yet a furtherembodiment, the device comprises 2, 3 or 4 nozzles, in some preferredembodiments, 2 nozzles, wherein each nozzle has an inner diameter at thepoint of exit from the device of about 0.2 mm to about 0.6 mm, or about0.30 mm to about 0.50 mm, for example, 0.35 mm. In some embodiments, theimpact pressure applied by each of the one or more jets at the targetsurface is about 0.4 MPa (58.1 psig) to about 0.5 MPa (72.5 psig), about0.41 (59.5 psig) to about 0.47 MPa (68.2 psig), about 0.42 (60.9 psig)to about 0.46 MPa (66.7 psig), or about 0.43 (62.4 psig) to about 0.45MPa (65.3 psig).

In some embodiments, there is provided a method of depositing apharmaceutical formulation containing a small molecule drug to thesubmucosa and/or mucosa of the small intestine of the subject. In someembodiments, the small molecule has a molecular weight of about 50 Da toabout 1500 Da, and the internal pressure on the pharmaceuticalformulation, prior to release from the device (i.e., the peak fluidpressure), is at least about 100 psig. In some embodiments, the internalpressure is at least about 150 psig. In some embodiments, the internalpressure is at least about 200 psig. In some embodiments, the internalpressure is at least about 220 psig. In some embodiments, the internalpressure is about 150 psig to about 450 psig, about 150 psig to about400 psig, about 150 psig to about 375 psig, about 150 psig to about 350psig, about 150 psig to about 325 psig, or about 150 psig to about 300psig. In other embodiments, the internal pressure for delivering thesmall molecule drug is about 175 psig to about 450 psig, about 175 psigto about 400 psig, about 175 psig to about 375 psig, about 175 psig toabout 350 psig, about 175 psig to about 325 psig, or about 175 psig toabout 300 psig. In other embodiments, the internal pressure fordelivering the small molecule drug is about 200 psig to about 450 psig,about 200 psig to about 400 psig, about 200 psig to about 375 psig,about 200 psig to about 350 psig, about 200 to about 325 psig, or about200 psig to about 300 psig. In other embodiments, the internal pressurefor delivering the small molecule drug is about 220 psig to about 450psig, about 220 psig to about 400 psig, about 220 psig to about 375psig, about 220 psig to about 350 psig, about 220 psig to about 325psig, or about 220 psig to about 300 psig. In other embodiments, theinternal pressure for delivering the small molecule drug is about 225psig to about 450 psig, about 225 psig to about 400 psig, about 225 psigto about 375 psig, about 225 psig to about 350 psig, about 225 psig toabout 325 psig, or about 225 psig to about 300 psig.

In some embodiments, there is provided a method of depositing apharmaceutical formulation containing a medium sized drug or peptide tothe submucosa and/or the mucosa (e.g., into the lamina propria) of thesmall intestine of the subject. In some embodiments, the drug has amolecular weight is greater than about 1500 Da and less than about 20kDa, less than about 30 kDa, less than about 40 kDa, less than about 50kDa or less than about 60 kDa. In some embodiments, the internalpressure on the pharmaceutical formulation, prior to release from thedevice (i.e., the peak fluid pressure), is at least about 150 psig. Insome embodiments, the internal pressure is at least about 200 psig. Insome embodiments, the internal pressure is at least about 220 psig. Insome embodiments, the internal pressure is at least about 225 psig. Insome embodiments, the internal pressure is about 200 psig to about 450psig, about 200 psig to about 400 psig, about 200 psig to about 375psig, about 200 psig to about 350 psig, about 200 psig to about 325psig, or about 200 psig to about 300 psig. In other embodiments, theinternal pressure is about 220 psig to about 450 psig, about 220 psig toabout 400 psig, about 220 psig to about 375 psig, about 220 psig toabout 350 psig, about 220 psig to about 325 psig, or about 220 psig toabout 300 psig. In other embodiments, the internal pressure is about 225psig to about 450 psig, about 225 psig to about 400 psig, about 225 psigto about 375 PSIG, about 225 psig to about 350 psig, about 225 psig toabout 325 psig, or about 225 psig to about 300 psig. In otherembodiments, the internal pressure is about 250 psig to about 450 psig,about 250 psig to about 400 psig, about 250 psig to about 375 psig,about 250 psig to about 350 psig, about 250 psig to about 325 psig, orabout 250 psig to about 300 psig. In other embodiments, the internalpressure is about 275 psig to about 450 psig, about 275 psig to about400 psig, about 275 psig to about 375 psig, about 275 psig to about 350psig, about 275 psig to about 325 psig, or about 275 psig to about 300psig. In other embodiments, the internal pressure is about 300 psig toabout 450 psig, about 300 psig to about 400 psig, about 300 psig toabout 375 psig, about 300 psig to about 350 psig, or about 300 psig toabout 325 psig.

In some embodiments, there is provided a method of depositing apharmaceutical formulation containing a large drug, such a therapeuticprotein or antibody, to the submucosa and/or the mucosa (e.g., into thelamina propria) of the small intestine of the subject. In someembodiments, the drug has a molecular weight is at least about 20 kDa,at least about 30 kDa, at least about 40 kDa, at least about 50 kDa orat least about 60 kDa. In some embodiments, the drug has a molecularweight ranging from about 20 kDa to about 200 kDa, from about 20 kDa toabout 175 kDa, or from about 20 kDa to about 150 kDa. In some otherembodiments, the drug has a molecular weight ranging from about 60 kDato about 200 kDa, from about 60 kDa to about 175 kDa, or from about 60kDa to about 150 kDa. In some embodiments, the internal pressure on thepharmaceutical formulation, prior to release from the device (i.e., thepeak fluid pressure), is at least about 225 psig. In some embodiments,the internal pressure is at least about 230 psig. In some embodiments,the internal pressure is at least about 235 psig, at least about 240psig, at least about 245 psig, or at least about 250 psig. In someembodiments, the internal pressure is at least about 275 psig, at leastabout 300 psig, or at least about 320 psig. In some embodiments, theinternal pressure is about 225 psig to about 500 psig, about 225 psig toabout 475 psig, about 225 psig to about 450 psig, about 225 psig toabout 425 psig, about 225 psig to about 400 psig, about 225 psig toabout 375 psig, about 225 psig to about 350 psig, or about 225 psig toabout 325 psig. In some embodiments, the internal pressure is about 250psig to about 500 psig, about 250 psig to about 475 psig, about 250 psigto about 450 psig, about 250 psig to about 425 psig, about 250 psig toabout 400 psig, about 250 psig to about 375 psig, about 250 psig toabout 350 psig, or about 250 psig to about 325 psig. In someembodiments, the internal pressure is about 275 psig to about 500 psig,about 275 psig to about 475 psig, about 275 psig to about 450 psig,about 275 psig to about 425 psig, about 275 psig to about 400 psig,about 275 psig to about 375 psig, about 275 psig to about 350 psig, orabout 275 psig to about 325 psig. In some embodiments, the internalpressure is about 300 psig to about 500 psig, about 300 psig to about475 psig, about 300 psig to about 450 psig, about 300 psig to about 425psig, about 300 psig to about 400 psig, about 300 psig to about 375psig, about 300 psig to about 350 psig, or about 300 psig to about 325psig. In some embodiments, the internal pressure is about 320 psig toabout 500 psig, about 320 psig to about 475 psig, about 320 psig toabout 450 psig, about 320 psig to about 425 psig, about 320 psig toabout 400 psig, about 320 psig to about 375 psig, or about 320 psig toabout 350 psig.

(I) A first set of nonlimiting embodiments includes:

1. An ingestible device, comprising:

a storage reservoir configured to store a dispensable substance; and

a pressurized chamber configured so that, when a restraining force isremoved one or more openings in the ingestible device become revealed,and the dispensable substance exits the ingestible device via theopenings in the ingestible device.

2. The ingestible device of embodiment 1, further comprising a pistonconfigured so that, when the restraining force is removed, the pistonmoves to force the dispensable substance out of the ingestible devicevia the openings.

3. The ingestible device of embodiment 1 or 2, wherein the storagereservoir stores the dispensable substance.

4. The ingestible device of any of the preceding embodiments, whereinthe restraining force is provided by restraining elements, wherein therestraining elements have a first state in which they are configured toprevent the dispensable substance from exiting the ingestible device viathe openings, and a second state in which they are configured to allowthe dispensable substance to exit the ingestible device via theopenings.

5. The ingestible device of embodiment 4, wherein the restrainingelements comprise an enteric material.

6. The ingestible device of embodiment 5, wherein the restrainingelements comprise one or more of polyvinyl acetate phthalate,methacrylic acid, methacrylic copolymers, cellulose acetate phthalate,acrylate copolymer, or cellulose acetate phthalate.

7. The ingestible device of any one of embodiments 4 to 6, wherein therestraining elements comprise at least one pin.

8. The ingestible device of any one of embodiments 4 to 7, wherein therestraining elements comprise at least one dowel, clasp, clamp, flange,or rivet.

9. The ingestible device of any one of embodiments 4 to 8, wherein therestraining elements are configured to transition from the first stateto the second state when the restraining elements are exposed to atriggering condition.

10. The ingestible device of embodiment 9, wherein the triggeringcondition relates to a condition of the GI tract.

11. The ingestible device of embodiment 10, wherein the condition of theGI tract comprises at least one condition selected from the groupconsisting of temperature, pH, presence of an enzyme, and time.

12. The ingestible device of embodiment 11, wherein the condition of theGI tract is a pH of greater than 5.

13. The ingestible device of any one of the preceding embodiments,wherein the restraining elements comprise a first type of restrainingelement and a second type of restraining element different from thefirst type of restraining element.

14. The ingestible device of embodiment 13, wherein the first type ofrestraining elements are configured to transition to their second statebefore the second type of restraining element transitions to its secondstate.

15. The ingestible device of any one of the preceding embodiments,further comprising an enteric coating on the housing of the ingestibledevice.

16. The ingestible device of any one of the preceding embodiments,wherein the pressurized chamber has an inlet configured to permit fluidto enter the pressurized chamber.

17. The ingestible device of embodiment 16, further comprising a valvewithin the inlet configured to regulate flow into the pressurizedchamber.

18. The ingestible device of embodiment 17, wherein the valve is a checkvalve.

19. The ingestible device of embodiment 17, wherein the valve is anumbrella valve or a duckbill valve.

20. The ingestible device of any one of the preceding embodiments,wherein the ingestible device comprises a housing.

21. The ingestible device of embodiment 20, wherein the housing isconfigured to maintain its mechanical integrity during use of theingestible device.

22. The ingestible device of embodiment 1, wherein the dispensablesubstance comprises a therapeutic agent comprising small molecules andlarge molecules including biologic drugs, proteins including fusionproteins, peptides including cyclic peptides, cells including stemcells, and nucleic acids such as inhibitory nucleic acids, antisensenucleic acids, siRNA, ribozymes.

23. The ingestible device of embodiment 1, wherein the restrainingelements are comprise a first type of restraining element and a secondtype of restraining element.

24. The ingestible device of embodiment 1, wherein the dispensablesubstance exits the device with sufficient velocity to pass through themucosa of mammalian gastrointestinal tissue.

25. The ingestible device of the preceding embodiments, wherein theopening is a nozzle with a rounded cross section.

26. The ingestible device of embodiment 25, wherein the first actuationcomponent is configured to actuate before the second actuationcomponent.

(II) A second set of nonlimiting embodiments include the following:

1. An ingestible device, comprising:

a housing;

an enteric coating on the housing; and

a storage reservoir within the housing,

wherein the storage reservoir is configured to store a dispensablesubstance.

2. The ingestible device of embodiment 1, further comprising a triggermechanism configured to cause the dispensable substance within thestorage reservoir to be released under triggering conditions.

3. The ingestible device of embodiment 1, further comprising a pistonconfigured so that, when the restraining force is removed from thepressurized chamber, the piston moves to force the dispensable substanceout of the ingestible device via the openings.

4. The ingestible device of any one of embodiments 1 to 3, wherein therestraining force is provided by restraining elements, wherein therestraining elements have a first state in which they are configured toprevent the dispensable substance from exiting the ingestible device viathe openings, and a second state in which they are configured to allowthe dispensable substance to exit the ingestible device via theopenings.

5. The ingestible device of embodiment 4, wherein the restrainingelements comprise an enteric material.

6. The ingestible device of embodiment 5, wherein the restrainingelements comprise one or more of polyvinyl acetate phthalate,methacrylic acid, methacrylic copolymers, cellulose acetate phthalate,acrylate copolymer, or cellulose acetate phthalate.

7. The ingestible device of any one of embodiments 1 to 6, wherein therestraining elements comprise at least one pin.

8. The ingestible device of any one of embodiments 1 to 6, wherein therestraining elements comprise at least one dowel, clasp, clamp, flange,or rivet.

9. The ingestible device of any one of embodiments 1 to 6, wherein therestraining elements are configured to transition from the first stateto the second state when the restraining elements are exposed to atriggering condition.

10. The ingestible device of embodiment 9, wherein the triggeringcondition relates to a condition of the GI tract.

11. The ingestible device of embodiment 10, wherein the condition of theGI tract comprises at least one condition selected from the groupconsisting of temperature, pH, presence of an enzyme, and time.

12. The ingestible device of embodiment 11, wherein the condition of theGI tract is a pH of greater than 5.

13. The ingestible device of any one of embodiments 1 to 12, wherein therestraining elements are comprise a first type of restraining elementand a second type of restraining element different from the first typeof restraining element.

14. The ingestible device of embodiment 13, wherein the first type ofrestraining elements are configured to transition to their second statebefore the second type of restraining element transitions to its secondstate.

15. The ingestible device of any one of embodiments 1 to 14, wherein thepressurized chamber has an inlet configured to permit fluid to enter thepressurized chamber.

16. The ingestible device of embodiment 15, further comprising a valvewithin the inlet configured to regulate flow into the pressurizedchamber.

17. The ingestible device of embodiment 16, wherein the valve is a checkvalve.

18. The ingestible device of embodiment 16, wherein the valve is anumbrella valve or a duckbill valve.

19. The ingestible device of any one of embodiments 1 to 18, wherein thedispensable substance comprises a therapeutic agent comprising smallmolecules and large molecules including biologic drugs, proteinsincluding fusion proteins, peptides including cyclic peptides, cellsincluding stem cells, and nucleic acids such as inhibitory nucleicacids, antisense nucleic acids, siRNA, ribozymes.

20. The ingestible device of any one of embodiments 1 to 19, wherein theopening is a nozzle with a rounded cross section.

21. The ingestible device of embodiment 20, wherein the first actuationcomponent is configured to actuate before the second actuationcomponent.

(III) A third set of nonlimiting embodiments include the following:

1. An ingestible device, comprising:

a housing having a first portion and a second portion;

a first actuation component on the housing;

a second actuation component within the housing; and

a storage reservoir located within the housing,

wherein the storage reservoir is configured to store a dispensablesubstance, and the housing has an opening in fluid communication withthe storage reservoir.

2. The ingestible device of embodiment 1, wherein the first actuationcomponent is an enteric coating.

3. The ingestible device of embodiment 1, wherein the second actuationcomponent is a restraining mechanism configured to keep the firstportion and the second portion of the housing in an open position.

4. The ingestible device of embodiment 3, wherein the second actuationcomponent comprises an enteric material.

5. The ingestible device of any one of embodiments 1 to 4, wherein thefirst and second actuation components are configured to cause thedispensable substance within the storage reservoir to be released undertriggering conditions.

6. The ingestible device of any one of embodiments 1 to 5, wherein thefirst actuation component has a first triggering condition differentfrom a second triggering condition of the second actuation component.

7. The ingestible device of embodiment 6, wherein the first and secondtriggering conditions relate to first and second conditions of the GItract.

8. The ingestible device of embodiment 7, wherein the condition of theGI tract comprises at least one condition selected from the groupconsisting of temperature, pH, presence of an enzyme, and time.

9. The ingestible device of embodiment 8, wherein the first condition ofthe GI tract is a pH of greater than 1 and the second condition of theGI tract is a pH of greater than 5.

10. The ingestible device of any one of embodiments 1 to 9, wherein thesecond actuation component comprises one or more of polyvinyl acetatephthalate, methacrylic acid, methacrylic copolymers, cellulose acetatephthalate, acrylate copolymer, or cellulose acetate phthalate.

11. The ingestible device of any one of embodiments 1 to 10, wherein thesecond actuation component comprises at least one pin.

12. The ingestible device of any one of embodiments 1 to 10, wherein thesecond actuation component comprises at least one dowel, clasp, clamp,flange, or rivet.

13. The ingestible device of any one of embodiments 1 to 12, wherein theopening is a nozzle with a rounded cross section.

14. The ingestible device of embodiment 13, wherein the first actuationcomponent is configured to actuate before the second actuationcomponent.

(IV) A fourth set of nonlimiting embodiments include the following:

1. An ingestible device, comprising:

a storage reservoir configured to store a dispensable substance; and

a pressurized chamber configured so that, when a restraining force isremoved one or more openings in the ingestible device become revealed,and the dispensable substance exits the drug delivery device via theopenings in the ingestible device.

2. The ingestible device of embodiment 1, further comprising a pistonconfigured so that, when the restraining force is removed, the pistonmoves to force the dispensable substance out of the ingestible devicevia the openings.

3. The ingestible device of embodiment 1 or claim 2, wherein the storagereservoir stores the dispensable substance.

4. The ingestible device of the preceding embodiments, wherein therestraining force is provided by restraining elements, wherein therestraining elements have a first state in which they are configured toprevent the dispensable substance from exiting the ingestible device viathe openings, and a second state in which they are configured to allowthe dispensable substance to exit the ingestible device via theopenings.

5. The ingestible device of embodiment 4, wherein the restrainingelements comprise an enteric material.

6. The ingestible device of embodiment 5, wherein the restrainingelements comprise one or more of polyvinyl acetate phthalate,methacrylic acid, methacrylic copolymers, cellulose acetate phthalate,acrylate copolymer, or cellulose acetate phthalate.

7. The ingestible device of embodiments 4-6, wherein the restrainingelements comprise at least one pin.

8. The ingestible device of embodiments 4-7, wherein the restrainingelements comprise at least one dowel, clasp, clamp, flange, or rivet.

9. The ingestible device of any one of embodiments 4-8, wherein therestraining elements are configured to transition from the first stateto the second state when the restraining elements are exposed to atriggering condition.

10. The ingestible device of embodiment 9, wherein the triggeringcondition relates to a condition of the GI tract.

11. The ingestible device of embodiment 10, wherein the condition of theGI tract comprises at least one condition selected from the groupconsisting of temperature, pH, presence of an enzyme, and time.

12. The ingestible device of embodiment 11, wherein the condition of theGI tract is a pH of greater than 5.

13. The ingestible device of any of the preceding embodiments, whereinthe restraining elements comprise a first type of restraining elementand a second type of restraining element different from the first typeof restraining element.

14. The ingestible device of embodiment 13, wherein the first type ofrestraining elements are configured to transition to their second statebefore the second type of restraining element transitions to its secondstate.

15. The ingestible device of the preceding embodiments, furthercomprising an enteric coating on the housing of the ingestible device.

16. The ingestible device of the preceding embodiments, wherein thepressurized chamber has an inlet configured to permit fluid to enter thepressurized chamber.

17. The ingestible device of embodiment 16, further comprising a valvewithin the inlet configured to regulate flow into the pressurizedchamber.

18. The ingestible device of embodiment 17, wherein the valve is a checkvalve.

19. The ingestible device of embodiment 17, wherein the valve is anumbrella valve or a duckbill valve.

20. The ingestible device of the preceding embodiments, wherein theingestible device comprises a housing.

21. The ingestible device of embodiment 20, wherein the housing isconfigured to maintain its mechanical integrity during use of theingestible device.

22. The ingestible device of embodiment 1, wherein the dispensablesubstance comprises a therapeutic agent comprising small molecules andlarge molecules including biologic drugs, proteins including fusionproteins, peptides including cyclic peptides, cells including stemcells, and nucleic acids such as inhibitory nucleic acids, antisensenucleic acids, siRNA, ribozymes.

23. The ingestible device of embodiment 1, wherein the restrainingelements are comprise a first type of restraining element and a secondtype of restraining element.

24. An ingestible device, comprising:

a housing;

an enteric coating on the housing; and

a storage reservoir within the housing,

wherein the storage reservoir is configured to store a dispensablesubstance.

25. The ingestible device of embodiment 24, further comprising a triggermechanism configured to cause the dispensable substance within thestorage reservoir to be released under triggering conditions.

26. The ingestible device of embodiment 24, further comprising a pistonconfigured so that, when the restraining force is removed from thepressurized chamber, the piston moves to force the dispensable substanceout of the ingestible device via the openings.

27. The ingestible device of embodiments 24-26, wherein the restrainingforce is provided by restraining elements, wherein the restrainingelements have a first state in which they are configured to prevent thedispensable substance from exiting the ingestible device via theopenings, and a second state in which they are configured to allow thedispensable substance to exit the ingestible device via the openings.

28. The ingestible device of embodiment 27, wherein the restrainingelements comprise an enteric material.

29. The ingestible device of embodiment 28, wherein the restrainingelements comprise one or more of polyvinyl acetate phthalate,methacrylic acid, methacrylic copolymers, cellulose acetate phthalate,acrylate copolymer, or cellulose acetate phthalate.

30. The ingestible device of embodiments 24-29, wherein the restrainingelements comprise at least one pin.

31. The ingestible device of embodiments 24-29, wherein the restrainingelements comprise at least one dowel, clasp, clamp, flange, or rivet.

32. The ingestible device of embodiments 24-29, wherein the restrainingelements are configured to transition from the first state to the secondstate when the restraining elements are exposed to a triggeringcondition.

33. The ingestible device of embodiment 32, wherein the triggeringcondition relates to a condition of the GI tract.

34. The ingestible device of embodiment 33, wherein the condition of theGI tract comprises at least one condition selected from the groupconsisting of temperature, pH, presence of an enzyme, and time.

35. The ingestible device of embodiment 34, wherein the condition of theGI tract is a pH of greater than 5.

36. The ingestible device of embodiments 24-35, wherein the restrainingelements are comprise a first type of restraining element and a secondtype of restraining element different from the first type of restrainingelement.

37. The ingestible device of embodiment 36, wherein the first type ofrestraining elements are configured to transition to their second statebefore the second type of restraining element transitions to its secondstate.

38. The ingestible device of embodiments 24-37, wherein the pressurizedchamber has an inlet configured to permit fluid to enter the pressurizedchamber.

39. The ingestible device of embodiment 38, further comprising a valvewithin the inlet configured to regulate flow into the pressurizedchamber.

40. The ingestible device of embodiment 39, wherein the valve is a checkvalve.

41. The ingestible device of embodiment 39, wherein the valve is anumbrella valve or a duckbill valve.

42. The ingestible device of embodiments 24-41, wherein the dispensablesubstance comprises a therapeutic agent comprising small molecules andlarge molecules including biologic drugs, proteins including fusionproteins, peptides including cyclic peptides, cells including stemcells, and nucleic acids such as inhibitory nucleic acids, antisensenucleic acids, siRNA, ribozymes.

43. An ingestible device, comprising:

a housing having a first portion and a second portion;

a first actuation component on the housing;

a second actuation component within the housing; and

a storage reservoir located within the housing,

wherein the storage reservoir is configured to store a dispensablesubstance, and the housing has an opening in fluid communication withthe storage reservoir.

44. The ingestible device of embodiment 43, wherein the first actuationcomponent is an enteric coating.

45. The ingestible device of embodiment 43, wherein the second actuationcomponent is a restraining mechanism configured to keep the firstportion and the second portion of the housing in an open position.

46. The ingestible device of embodiment 45, wherein the second actuationcomponent comprises an enteric material.

47. The ingestible device of embodiments 43-46, wherein the first andsecond actuation components are configured to cause the dispensablesubstance within the storage reservoir to be released under triggeringconditions.

48. The ingestible device of embodiments 43-47, wherein the firstactuation component has a first triggering condition different from asecond triggering condition of the second actuation component.

49. The ingestible device of embodiment 48, wherein the first and secondtriggering conditions relate to first and second conditions of the GItract.

50. The ingestible device of embodiment 49, wherein the condition of theGI tract comprises at least one condition selected from the groupconsisting of temperature, pH, presence of an enzyme, and time.

51. The ingestible device of embodiment 50, wherein the first conditionof the GI tract is a pH of greater than 1 and the second condition ofthe GI tract is a pH of greater than 5.

52. The ingestible device of embodiment 43-51, wherein the secondactuation component comprises one or more of polyvinyl acetatephthalate, methacrylic acid, methacrylic copolymers, cellulose acetatephthalate, acrylate copolymer, or cellulose acetate phthalate.

53. The ingestible device of embodiments 43-52, wherein the secondactuation component comprises at least one pin.

54. The ingestible device of embodiments 43-52, wherein the secondactuation component comprises at least one dowel, clasp, clamp, flange,or rivet.

55. The ingestible device of the preceding embodiments, wherein theopening is a nozzle with a rounded cross section.

56. The ingestible device of embodiment 55, wherein the first actuationcomponent is configured to actuate before the second actuationcomponent.

57. The ingestible device of embodiment 1, wherein the dispensablesubstance exits the device with sufficient velocity to penetrate themucosa of mammalian gastrointestinal tissue.

A number of embodiments have been described. Nevertheless, variousmodifications may be made without departing from the spirit and scope ofthe disclosure. Accordingly, other embodiments are within the scope ofthe following claims.

1-832. (canceled)
 833. An ingestible device comprising: a storagereservoir in a housing; a dispensable substance in the storagereservoir; one or more nozzles in the housing connecting into thestorage reservoir, each nozzle extending through a sidewall of thehousing; a gas cylinder in the housing, the gas cylinder containing acompressed gas; and a piercer for piercing the gas cylinder to releasethe compressed gas from the gas cylinder into the housing.
 834. Theingestible device of claim 833 wherein the ingestible device isconfigured to deliver the dispensable substance as a jet through eachnozzle with a peak jet power of each jet of about one Watt to aboutthree Watts.
 835. The ingestible device of claim 833 further including atriggering component which triggers release of the compressed gas fromthe gas cylinder after the ingestible device is ingested.
 836. Theingestible device of claim 833 further including a sliding piston in thehousing between the gas cylinder and the storage reservoir.
 837. Theingestible device of claim 833 wherein the ingestible device isconfigured to provide an internal pressure of about 225 psig to about425 psig.
 838. The ingestible device of claim 833 wherein the ingestibledevice is configured to provide a peak fluid pressure on the dispensablesubstance of about 300 psig to about 375 psig.
 839. The ingestibledevice of claim 833 wherein the ingestible device is configured todeliver the dispensable substance at a mean jet velocity of from about10 m/s to about 50 m/s.
 840. The ingestible device of claim 833 whereinthe ingestible device is configured to deliver the dispensable substanceto tissue of the GI tract of a patient at a peak jet force of about 0.09N to about 0.15 N.
 841. The ingestible device of claim 833 wherein theingestible device is configured to directly deliver the dispensablesubstance into the submucosa of the gastrointestinal tract of a patient.842. The ingestible device of claim 833 wherein the device is configuredto release a dispensable substance volume of 50 microliters to 500microliters.
 843. The ingestible device of claim 833 wherein one or moreof the nozzles has a nozzle diameter of 0.2 to 2 mm.
 844. An ingestibledevice comprising: a storage reservoir in a housing; a dispensablesubstance in the storage reservoir; one or more nozzles in the housingconnecting into the storage reservoir, each nozzle extending through asidewall of the housing; a drive force generator in the housing; whereinthe ingestible device is configured to deliver the dispensable substanceas a jet through each nozzle with a peak jet power of each jet of aboutone Watt to about three Watts.
 845. The ingestible device of claim 844wherein the drive force generator comprises a gas cylinder in thehousing, the gas cylinder containing a compressed gas, furthercomprising a piercer for piercing the gas cylinder to release thecompressed gas from the gas cylinder into the housing.
 846. Theingestible device of claim 845 further including a triggering componentwhich triggers release of the compressed gas from the gas cylinder afterthe ingestible device is ingested.
 847. The ingestible device of claim846 further including a sliding piston in the housing between the gascylinder and the storage reservoir.
 848. The ingestible device of claim844 wherein the ingestible device is configured to provide an internalpressure of about 225 psig to about 425 psig.
 849. The ingestible deviceof claim 844 wherein the ingestible device is configured to provide apeak fluid pressure on the dispensable substance of about 300 psig toabout 375 psig.
 850. The ingestible device of claim 844 wherein theingestible device is configured to deliver the dispensable substance ata mean jet velocity of from about 10 m/s to about 50 m/s.
 851. Theingestible device of claim 844 wherein the ingestible device isconfigured to deliver the dispensable substance to tissue of the GItract of a patient at a peak jet force of about 0.09 N to about 0.15 N.852. The ingestible device of claim 844 wherein the ingestible device isconfigured to directly deliver the dispensable substance into thesubmucosa of the gastrointestinal tract of a patient.
 853. Theingestible device of claim 844 wherein the device is configured torelease a dispensable substance volume of 50 microliters to 500microliters.
 854. The ingestible device of claim 844 wherein one or moreof the nozzles has a nozzle diameter of 0.2 to 2 mm.
 855. An ingestibledevice comprising: a storage reservoir in a housing; a dispensablesubstance in the storage reservoir; one or more nozzles in the housingconnecting into the storage reservoir, each nozzle extending through asidewall of the housing; a drive force generator in the housing; whereinthe ingestible device is configured to provide an internal pressure ofabout 225 psig to about 425 psig.
 856. The ingestible device of claim855 wherein the ingestible device is configured to deliver thedispensable substance as a jet through each nozzle with a peak jet powerof each jet of about one Watt to about three Watts.
 857. The ingestibledevice of claim 855 wherein the drive force generator comprises a gascylinder in the housing, the gas cylinder containing a compressed gas,further comprising a piercer for piercing the gas cylinder to releasethe compressed gas from the gas cylinder into the housing.
 858. Theingestible device of claim 857 further including a triggering componentwhich triggers release of the compressed gas from the gas cylinder afterthe ingestible device is ingested.
 859. The ingestible device of claim855 further including a sliding piston in the housing between the gascylinder and the storage reservoir.
 860. The ingestible device of claim855 wherein the ingestible device is configured to provide a peak fluidpressure on the dispensable substance of about 300 psig to about 375psig.
 861. The ingestible device of claim 855 wherein the ingestibledevice is configured to deliver the dispensable substance at a mean jetvelocity of from about 10 m/s to about 50 m/s.
 862. The ingestibledevice of claim 855 wherein the ingestible device is configured todeliver the dispensable substance to tissue of the GI tract of a patientat a peak jet force of about 0.09 N to about 0.15 N.
 863. The ingestibledevice of claim 855 wherein the ingestible device is configured todirectly deliver the dispensable substance into the submucosa of thegastrointestinal tract of a patient.
 864. The ingestible device of claim855 wherein the device is configured to release a dispensable substancevolume of 50 microliters to 500 microliters.
 865. The ingestible deviceof claim 855 wherein one or more of the nozzles has a nozzle diameter of0.2 to 2 mm.